KR20160018811A - Metalloenzyme Inhibitor Compounds - Google Patents

Abstract

The present invention discloses a compound having a metal enzyme-modulating activity and a method for treating a disease, disorder or symptom associated with the metal enzyme.

Description

Metalloenzyme Inhibitor Compounds < RTI ID = 0.0 >

The invention is directed to a compound (e. G., Any one of the compounds described herein), a method of modulating the activity of a metalloenzyme, and a method of treating a disease, disorder or symptom thereof. Such methods may include the compounds of the present invention.

Organisms have been developed by strictly controlled processes that specifically introduce metals, transport them to intracellular storage sites, and ultimately transport them to sites of use. One of the most important functions of metals such as zinc and iron in biological systems is the ability to activate metal enzymes. Metal enzymes are enzymes that bind metal ions to the enzyme active site and utilize metals as part of the catalytic process. More than one third of all enzymes identified are metal enzymes.

The function of the metal enzyme is highly dependent on the presence of metal ions in the active site of the enzyme. It is well known that substances that bind to and inactivate the active site rapidly reduce the activity of the enzyme. The natural world applies the same strategy to reduce the activity of certain metal enzymes during periods when enzyme activity is unnecessary. For example, the TIMP protein (a tissue inhibitor of metalloprotease) binds to zinc ions in the active site of various substrate metalloprotease enzymes, inhibiting enzyme activity. The pharmaceutical industry has been using this strategy to design treatments. For example, the azole antifungal agents fluconazole and voriconazole contain the 1- (1,2,4-triazole) group, which is the target enzyme lanosterol dimethyridine ( lanosterol demethylase) to inactivate the enzyme by binding to the heme iron present in the active site. Other examples include zinc-binding hydroxamic acid groups coupled to most of the disclosed inhibitors of matrix metalloproteinases and histone deacetylases .

In the design of clinically safe and effective metal enzyme inhibitors, the use of the most suitable metal-binding groups for specific targets and clinical indications is very important. Using a weakly binding metal-binding group, the potency can be sub-optimal. On the other hand, utilizing a very tightly binding metal-binding group, the selectivity for the target enzyme may be suboptimal compared to the related metal enzyme. The lack of optimal selectivity may cause clinical toxicity due to unintended inhibition of off-target metalloenzymes. One example of such clinical toxicity is the unintentional inhibition of human drug metabolizing enzymes such as CYP2C9, CYP2C19 and CYP3A4 due to azole antifungal agents such as fluconazole and voriconazole, which are currently available . Off-target inhibition is believed to be caused primarily by indiscriminate binding of iron to the active site of CYP2C9, CYP2C19, and CYP3A4 in the currently available 1- (1,2,4-triazole) . Another example of this is joint pain which is observed in many clinical trials of substrate metal enzyme inhibitors. It is believed that the toxicity is related to the inhibition of non-target metal enzymes because hydroxamic acid groups indiscriminately bind to zinc in non-target active sites.

Thus, the search for a metal-binding group that can achieve a better balance of efficacy and selectivity remains a major goal and provides a therapeutic and therapeutic option to address the current and unmet need for the treatment and prevention of diseases, disorders and symptoms thereof The realization of the method will be important.

The present invention relates to compounds (e. G., Those described below), methods of modulating the activity of metal enzymes, and methods of treating diseases, disorders and symptoms thereof. The methods may include the following compounds.

Embodiments of the invention described below with respect to the various preferred embodiments of the present invention can be taken alone or in combination with one or more embodiments of the invention or various preferred choices and each combination is understood as explicitly described below .

A compound of formula (I), or a salt, solvate, hydrate or prodrug thereof, wherein:

R ₁ is halo;

R ₂ is halo;

Each R ₃ is independently selected from the group consisting of cyano, haloalkyl, alkoxy, halo, haloalkoxy, hydroxy, amino, -NR ₆ R ₉ , -SR ₁₀ , -C (O) R ₁₀ , optionally substituted _{aryl-alkoxy, - C (O) NR 6} R 7, -CH (OH) - haloalkyl, optionally substituted alkyl, hydroxyalkyl, optionally substituted alkoxyalkyl, isocyano, cycloalkylamino Optionally substituted aryloxyalkyl, optionally substituted arylalkylthio, haloalkylthio, optionally substituted arylalkylsulfonyl, optionally substituted arylalkylsulfinyl, optionally substituted heteroarylalkoxy, optionally substituted aryloxyalkyl, optionally substituted arylalkylthio, / RTI > or haloalkylcarbonyl;

n is 0, 1, 2 or 3;

Each R < ₄ > is independently aryl substituted with 0, 1, 2 or 3, independent R < ₈ >;

R < ₅ > is -C (O) alkyl substituted by H, alkyl, phosphato, phosphato, alkoxy phosphato or optionally one or two amino;

Each R < ₆ > is independently H or alkyl;

Each R < ₇ > is independently H, optionally substituted alkyl, optionally substituted haloalkyl, or optionally substituted arylalkyl;

Each R < ₈ > is independently optionally substituted alkyl, cyano, haloalkyl, alkoxy, halo, or haloalkoxy;

Each R ₉ is independently H, alkyl, -C (O) alkyl, -C (O) H, -C (O) haloalkyl, optionally substituted arylalkyl, or optionally substituted haloalkyl;

Each R < ₁₀ > is independently H, optionally substituted alkyl, optionally aryl, optionally substituted heterocycloalkyl, or optionally substituted arylalkyl;

,

,

,

, 또는

이고;Ar ₂ is

,

,

,

, or

ego;

이고;R ₁₁ is selected from optionally substituted phenyl, optionally substituted alkyl, optionally substituted thienyl, pyrrolyl, furanyl, optionally substituted pyridyl, -CH (OH) ) -Haloalkyl, optionally substituted arylalkyl, optionally substituted aryloxyalkyl, haloalkyl, haloalkoxyalkyl, optionally substituted indolyl, optionally substituted benzofuranyl, heterocycloalkyl, or

ego;

R ₁₂ is R ₄ , -C (O) R ₄ , -C (O) R ₇ , -SO ₂ R ₄ ;

MBG is an optionally substituted tetrazolyl, an optionally substituted triazolyl, an optionally substituted oxazolyl, an optionally substituted pyrimidinyl, an optionally substituted thiazolyl, or an optionally substituted pyrazolyl.

A compound of formula (V), or a salt, solvate, hydrate or prodrug thereof, wherein:

R < ₁ > is halo (e.g. fluorine);

R < ₂ > is halo (e.g., fluorine);

Each R ₃ is independently selected from the group consisting of cyano, haloalkyl, alkoxy, halo, haloalkoxy, hydroxy, amino, -NR ₆ R ₉ , -SR ₁₀ , -C (O) R ₁₀ , substituted _{aryl-alkoxy, -C (O) NR 6 R} 7, -CH (OH) - haloalkyl, an optionally substituted alkyl, hydroxyalkyl, optionally substituted alkoxyalkyl, isocyano, cycloalkyl aminocarbonyl Optionally substituted aryloxyalkyl, optionally substituted arylalkylthio, haloalkylthio, optionally substituted arylalkylsulfonyl, optionally substituted arylalkylsulfinyl, optionally substituted heteroarylalkoxy, optionally substituted aryloxyalkyl, optionally substituted arylalkylthio, Substituted arylthioalkyl, or haloalkylcarbonyl;

n is 0, 1, 2 or 3;

Each R _{4 is} independently aryl substituted with 0, 1, 2 or 3, independent R ₈ ;

Each R ₂₇ is independently alkyl, cycloalkyl, or aralkyl substituted with 0, 1, 2, or 3, independent R ₈ ;

R ₅ is H, alkyl, phosphato, phosphito, alkoxy phosphato, or -C (O) alkyl optionally substituted with 1 or 2 amino;

Each R < ₆ > is independently H or alkyl;

Each R < ₇ > is independently H, optionally substituted alkyl, optionally substituted haloalkyl, or optionally substituted arylalkyl;

Each R < ₈ > is independently optionally substituted alkyl, cyano, haloalkyl, alkoxy, halo, or haloalkoxy;

Each R ₉ is independently H, alkyl, -C (O) alkyl, -C (O) H, -C (O) haloalkyl, optionally substituted arylalkyl, or optionally substituted haloalkyl;

Each R < ₁₀ > is independently H, optionally substituted alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted arylalkyl;

,

,

,

, 또는

이고;Ar ₂ is

,

,

,

, or

ego;

이고;R ₁₁ is selected from the group consisting of optionally substituted phenyl, optionally substituted alkyl, optionally substituted thienyl, pyrrolyl, furanyl, optionally substituted pyridyl, -CH (OH) Alkyl, optionally substituted arylalkyl, optionally substituted aryloxyalkyl, haloalkyl, haloalkoxyalkyl, optionally substituted indolyl, optionally substituted benzofuranyl, heterocycloalkyl, or

ego;

R ₂₉ is R ₂₈ , -C (O) R ₄ , -C (O) R ₇ , -SO ₂ R ₄ ;

Each R ₂₈ is independently aryl, alkyl, cycloalkyl, or aralkyl each of which is substituted with 0, 1, 2 or 3, independent R ₈ ;

MBG is an optionally substituted tetrazolyl, an optionally substituted triazolyl, an optionally substituted oxazolyl, an optionally substituted pyrimidinyl, an optionally substituted thiazolyl, or an optionally substituted pyrazolyl.

Another aspect is a compound of formula (VI), or a salt, solvate, hydrate or prodrug thereof, wherein:

R < ₁ > is halo (e.g. fluorine);

R < ₂ > is halo (e.g., fluorine);

Each R < ₄ > is independently aryl substituted with 0, 1, 2 or 3, independent R < ₈ >;

Each R ₂₇ is independently alkyl, cycloalkyl, or aralkyl each of which is substituted with 0, 1, 2 or 3, independent R ₈ ;

R < ₅ > is -C (O) alkyl optionally substituted with H, alkyl, phosphato, phosphito, alkoxy phosphato or 1 or 2 amino;

Each R < ₇ > is independently H, optionally substituted alkyl, optionally substituted haloalkyl, or optionally substituted arylalkyl;

Each R < ₈ > is independently optionally substituted alkyl, cyano, haloalkyl, alkoxy, halo, or haloalkoxy;

또는

이고;Each R < ₃₄ >

or

ego;

Each R ₂₉ is independently R ₂₈ , -C (O) R ₄ , -C (O) R ₇ , -SO ₂ R ₄ ;

Each R < ₂₈ > is independently aryl, alkyl, cycloalkyl, or aralkyl each independently substituted with 0, 1, 2, or 3 independent R < ₈ >;

,

,

,

,

, 또는

이고;Each R < ₃₀ >

,

,

,

,

, or

ego;

Each X is independently O or S;

Each Y is independently OH, NH _2, or NH-SO ₂ -R _17, and;

Each n is independently 0, 1, 2, or 3;

Each o is independently 0, 1, 2, or 3;

Each p is independently 0, 1, 2, or 3;

Each t is independently 0, 1, 2, or 3;

Each R < ₃₁ > is independently:

,

,

,

,

,

, 또는

로 치환된 알킬;a) 1, 2, or 3 independent OH, haloalkoxy, optionally substituted heterocyclo, optionally substituted heteroaryl,

,

,

,

,

,

, or

≪ / RTI >

로 치환된 알콕시;b) an independent OR ₁₇ of 0, 1, 2, or 3; or

≪ / RTI >

;c)

;

   d) halo;

   e) haloalkyl;

   f) haloalkoxy; or

   g) optionally substituted heterocyclo;

Each R ₃₂ is independently:

   a) haloalkyl;

   b) halo;

,

,

,

,

, 또는

로 치환된 알킬; c) 0, 1, 2, or 3 independent OH, haloalkoxy, optionally substituted heterocyclo, optionally substituted heteroaryl,

,

,

,

,

, or

≪ / RTI >

; 또는d)

; or

   e) haloalkoxy;

Each R < ₁₆ > is independently:

    a) 0, 1, 2, or 3 independently substituted aralkyl:

      (1) cyano;

      (2) halo;

;(3)

;

      (4) alkoxy;

      (5) haloalkyl;

      (6) haloalkoxy;

      (7) optionally substituted alkyl;

      (8) optionally substituted aryl;

      (9) optionally substituted heteroaryl; or

      (10) optionally substituted heterocyclyl;

b) OR ₁₇ ; or

    c) optionally substituted aryl;

이고, Each R < ₁₇ > is independently H, optionally substituted alkyl, haloalkyl, or

ego,

Each R < ₁₈ > is independently:

   a) independently substituted 0, 1, 2, or 3 aryl:

      (1) halo;

      (2) haloalkyl;

      (3) alkoxy;

      (4) haloalkoxy;

      (5) optionally substituted cycloalkyl;

      (6) optionally substituted heterocyclyl;

      (7) optionally substituted alkyl;

;(8)

;

(9) OR ₁₉ ;

(10) SR ₁₉ ;

      (11) optionally substituted heteroaryl; or

      (12) cyano;

   b) optionally substituted cycloalkyl;

   c) optionally substituted heteroaryl;

   d) optionally substituted heterocyclyl;

   e) optionally substituted alkyl;

   f) optionally substituted cycloalkylalkyl;

   g) optionally substituted cycloalkylalkoxy;

   h) haloalkyl;

   i) haloalkoxy;

   j) haloalkoxyalkyl;

; 또는k)

; or

   l) an optionally substituted aralkyl;

Each R < ₁₉ > is independently H, optionally substituted alkyl, or haloalkyl;

이고;Each R < ₂₀ > is independently H, optionally substituted alkyl, haloalkyl, or

ego;

이고;Each R < ₃₃ > is independently H, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkylcarbonyl, or

ego;

Each R < ₂₂ > is independently:

;a)

;

   b) optionally substituted alkyl;

   c) optionally substituted aryl;

   d) optionally substituted heteroaryl;

   e) optionally substituted cycloalkyl; or

   f) optionally substituted heterocyclyl;

이다.Each R < ₂₅ > is independently optionally substituted aryl; Optionally substituted arylalkyl, haloalkoxy, (haloalkoxy) alkyl, cycloalkyl, _{alkyl, -CH 2 CF 2 CF 3,} -CF 2 CF 3, or

to be.

Another aspect is a compound of formula (X), or a salt, solvate, hydrate or prodrug thereof, wherein:

R < ₁ > is halo (e.g., fluorine);

R < ₂ > is halo (e.g., fluorine);

Each R _{4 is} independently aryl substituted with 0, 1, 2 or 3, independent R ₈ ;

R ₅ is H, alkyl, phosphato, phosphito, alkoxy phosphato, or -C (O) alkyl optionally substituted with 1 or 2 amino;

Each R < ₇ > is independently H, optionally substituted alkyl, optionally substituted haloalkyl, or optionally substituted arylalkyl;

Each R < ₈ > is independently optionally substituted alkyl, cyano, haloalkyl, alkoxy, halo, or haloalkoxy;

또는

이고;Each R ₃₉ is independently

or

ego;

Each R ₂₉ is independently R ₂₈ , -C (O) R ₄ , -C (O) R ₇ , -SO ₂ R ₄ ;

Each R < ₂₈ > is independently aryl, alkyl, cycloalkyl, or aralkyl each of which is substituted independently with 0, 1, 2 or 3 R < ₈ >;

,

,

,

,

, 또는

이고;Each R < ₃₅ >

,

,

,

,

, or

ego;

Each X is independently O or S;

Each Y is independently OH, NH _2, or NH-SO ₂ -R _17, and;

Each n is independently 1, 2, or 3;

Each o is independently 0, 1, 2, or 3;

Each p is independently 0, 1, 2, or 3;

Each t is independently 0, 1, 2, or 3;

Each R < ₁₄ > is independently:

,

,

,

,

,

,또는

로 치환된 알킬;a) 1, 2, or 3 independent OH, haloalkoxy, optionally substituted heterocyclo, optionally substituted heteroaryl,

,

,

,

,

,

,or

≪ / RTI >

로 치환된 알콕시;b) 0, 1, 2, or 3 independent OR ₁₇ or

≪ / RTI >

; 또는c)

; or

   d) optionally substituted heterocyclo;

Each R ₃₂ is independently:

   a) haloalkyl;

   b) halo;

,

,

,

,

, 또는

로 치환된 알킬; c) 0, 1, 2, or 3 independent OH, haloalkoxy, optionally substituted heterocyclo, optionally substituted heteroaryl,

,

,

,

,

, or

≪ / RTI >

; 또는d)

; or

   e) haloalkoxy;

Each R < ₁₆ > is independently:

   a) 0, 1, 2, or 3 independently substituted aralkyl;

      (1) cyano;

      (2) halo;

;(3)

;

      (4) alkoxy;

      (5) haloalkyl;

      (6) haloalkoxy;

      (7) optionally substituted alkyl;

      (8) optionally substituted aryl;

      (9) optionally substituted heteroaryl; or

      (10) optionally substituted heterocyclyl;

b) OR ₁₇ ; or

   c) optionally substituted aryl;

이고;Each R < ₁₇ > is independently H, optionally substituted aryl, haloalkyl, or

ego;

Each R < ₁₈ > is independently:

   a) independently substituted 0, 1, 2, or 3 aryl:

      (1) halo;

      (2) haloalkyl;

      (3) alkoxy;

      (4) haloalkoxy;

      (5) optionally substituted cycloalkyl;

      (6) optionally substituted heterocyclyl;

      (7) optionally substituted alkyl;

; (8)

;

(9) OR ₁₉ ;

(10) SR ₁₉ ;

      (11) optionally substituted heteroaryl; or

      (12) cyano;

   b) optionally substituted cycloalkyl;

   c) optionally substituted heteroalkyl;

   d) optionally substituted heterocyclyl;

   e) optionally substituted alkyl;

   f) optionally substituted cycloalkyl;

   g) optionally substituted cycloalkylalkoxy;

   h) haloalkyl;

   i) haloalkoxy;

   j) haloalkoxyalkyl;

; 또는k)

; or

   l) an optionally substituted aralkyl;

Each R < ₁₉ > is independently H, optionally substituted alkyl, or haloalkyl;

이고,Each R < ₂₀ > is independently H, optionally substituted alkyl, or

ego,

이고,Each R ₃₃ is independently H, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkylcarbonyl, or

ego,

Each R < ₂₂ > is independently:

;a)

;

   b) optionally substituted alkyl;

          c) optionally substituted aryl;

          d) optionally substituted heteroaryl;

    e) optionally substituted cycloalkyl; or

   f) optionally substituted heterocyclyl;

Each R < ₂₅ > is independently optionally substituted aryl; Optionally substituted arylalkyl,

이다.Haloalkoxy, (haloalkoxy) alkyl, cycloalkyl, alkyl, CH ₂ CF ₂ CF ₃ , -CF ₂ CF ₃ ,

to be.

A compound of formula (I), or a salt, solvate, hydrate or prodrug thereof, wherein:

R < ₁ > is halo;

R ₂ is halo;

Each R ₃ is independently selected from the group consisting of cyano, haloalkyl, alkoxy, halo, haloalkoxy, hydroxy, amino, -NR ₆ R ₉ , -SR ₁₀ , -C (O) R ₁₀ , substituted _{arylalkyl, C (O) NR 6 R} 7, -CH (OH) - haloalkyl, optionally substituted alkyl, hydroxyalkyl, optionally substituted alkoxyalkyl, isocyano, cycloalkyl aminocarbonyl , Optionally substituted aryloxyalkyl, optionally substituted arylalkylthio, haloalkylthio, optionally substituted arylalkylsulfonyl, optionally substituted arylalkylsulfinyl, optionally substituted heteroarylalkoxy, optionally substituted arylalkylthio, Arylthioalkyl, or haloalkylcarbonyl;

n is 0, 1, 2 or 3;

Each R < ₄ > is independently aryl substituted with 0, 1, 2 or 3, independent R < ₈ >;

R ₅ is H, alkyl, phosphato, phosphito, alkoxy phosphato, or -C (O) alkyl optionally substituted with 1 or 2 amino;

Each R < ₆ > is independently H or alkyl;

Each R < ₇ > is independently H, optionally substituted alkyl, optionally substituted haloalkyl, or optionally substituted arylalkyl;

Each R < ₈ > is independently optionally substituted alkyl, cyano, haloalkyl, alkoxy, halo, or haloalkoxy;

Each R ₉ is independently H, alkyl, -C (O) alkyl, -C (O) H, -C (O) haloalkyl, optionally substituted arylalkyl, or optionally substituted haloalkyl;

Each R < ₁₀ > is independently H, optionally substituted alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted arylalkyl;

,

,

,

, 또는

이고;Ar ₂ is

,

,

,

, or

ego;

이고;R ₁₁ is selected from the group consisting of optionally substituted phenyl, optionally substituted alkyl, optionally substituted thienyl, pyrrolyl, furanyl, optionally substituted pyridyl, -CH (OH) Alkyl, optionally substituted arylalkyl, optionally substituted arylalkoxyalkyl, haloalkyl, haloalkoxyalkyl, optionally substituted indolyl, optionally substituted benzofuranyl, heterocycloalkyl, or

ego;

R ₂₉ is R ₂₈ , -C (O) R ₄ , -C (O) R ₇ , -SO ₂ R ₄ ;

Each R ₂₈ is independently aryl, alkyl, cycloalkyl, or aralkyl substituted with 0, 1, 2 or 3, independent R ₈ ;

MBG is an optionally substituted tetrazolyl, an optionally substituted triazolyl, an optionally substituted oxazolyl, an optionally substituted paradominyl, an optionally substituted thiazolyl, or an optionally substituted pyrazolyl.

Another aspect is a compound of formula (XI), or a salt, solvate, hydrate or prodrug thereof, wherein:

R < ₁ > is halo (e.g., fluorine);

R < ₂ > is halo (e.g., fluorine);

Each R < ₄ > is independently aryl substituted with 0, 1, 2 or 3, independent R < ₈ >;

R ₅ is H, alkyl, phosphato, phosphito, alkoxy phosphato, or -C (O) alkyl optionally substituted with 1 or 2 amino;

Each R < ₈ > is independently optionally substituted alkyl, cyano, haloalkyl, alkoxy, halo, or haloalkoxy;

또는

이고;Each R < ₃₆ >

or

ego;

Each n is independently 1, 2, or 3;

Each p is independently 0, 1, 2, or 3;

Each R < ₃₇ > is independently halo, haloalkyl, or haloalkoxy;

Each R < ₃₈ > is independently:

,

,

,

,

,

, 또는

로 치환된 알킬; a) 1, 2, or 3 independent OH, haloalkoxy, optionally substituted heterocyclo, optionally substituted heteroaryl,

,

,

,

,

,

, or

≪ / RTI >

로 치환된 알콕시;b) 0, 1, 2, or 3 independent OR ₁₇ or

≪ / RTI >

; 또는c)

; or

   d) optionally substituted heterocyclo;

이고;Each R < ₁₇ > is independently H, optionally substituted alkyl, haloalkyl, or

ego;

Each R < ₁₉ > is independently H, optionally substituted alkyl, or haloalkyl;

이다.Each R ₃₃ is independently H, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkylcarbonyl, or

to be.

In another aspect, n = 1. In another aspect, n = 2. In another aspect, n = 3.

Another aspect is a compound of formula (II), or a salt, solvate, hydrate, or prodrug thereof, wherein:

,

,

,

, 또는

이고;Each R < ₁₃ >

,

,

,

, or

ego;

Each X is independently O or S;

Each n is independently 0, 1, 2, or 3;

Each o is independently 0, 1, 2, or 3;

Each p is independently 0, 1, 2, or 3;

Each R < ₁₄ > is independently:

,

,

,

,

,또는

로 치환된 알킬; a) 1, 2, or 3 independent OH, haloalkoxy, optionally substituted heterocyclo, optionally substituted heteroaryl,

,

,

,

,

,or

≪ / RTI >

로 치환된 알콕시; 또는b) an independent OR ₁₇ of 0, 1, 2, or 3; or

≪ / RTI > or

이고; c)

ego;

Each R < ₁₅ > is independently:

   a) haloalkyl;

   b) halo;

,

,

,

,

, 또는

로 치환된 알킬; c) 0, 1, 2, or 3 independent OH, haloalkoxy, optionally substituted heterocyclo, optionally substituted heteroaryl,

,

,

,

,

, or

≪ / RTI >

이고; d)

ego;

Each R < ₁₆ > is independently:

   a) 0, 1, 2, or 3 independently substituted aralkyl:

      (1) cyano;

      (2) halo;

;(3)

;

      (4) alkoxy;

      (5) haloalkyl;

      (6) haloalkoxy;

      (7) optionally substituted alkyl;

      (8) optionally substituted aryl;

      (9) optionally substituted heteroaryl; or

      (10) optionally substituted heterocyclyl;

b) OR ₁₇ ; or

   c) optionally substituted aryl;

이다.Each R < ₁₇ > is independently H, optionally substituted alkyl, haloalkyl, or

to be.

Each R < ₁₈ > is independently:

   a) independently substituted 0, 1, 2, or 3 aryl:

      (1) halo;

      (2) haloalkyl;

      (3) alkoxy;

      (4) haloalkoxy;

      (5) optionally substituted cycloalkyl;

      (6) optionally substituted heterocyclyl;

      (7) optionally substituted alkyl;

;(8)

;

(9) OR ₁₉ ;

(10) SR ₁₉ ;

      (11) optionally substituted heteroaryl; or

      (12) cyano;

   b) optionally substituted cycloalkyl;

   c) optionally substituted heteroaryl;

   d) optionally substituted heterocyclyl;

   e) optionally substituted alkyl;

   f) optionally substituted cycloalkylalkyl;

   g) optionally substituted cycloalkylalkoxy;

   h) haloalkyl;

   i) haloalkoxy;

   j) haloalkoxyalkyl;

; 또는k)

; or

   l) an optionally substituted aralkyl;

Each R < ₁₉ > is independently H, optionally substituted alkyl, or haloalkyl;

이고;Each R < ₂₀ > is independently H, optionally substituted alkyl, haloalkyl, or

ego;

Each R < ₂₁ > is independently H, optionally substituted heteroaryl, optionally substituted

이고;Alkyl, haloalkyl, optionally substituted alkylcarbonyl, or < RTI ID = 0.0 >

ego;

Each R < ₂₂ > is independently:

이고;a)

ego;

         b) optionally substituted alkyl;

  c) optionally substituted aryl;

  d) optionally substituted heteroaryl;

  e) optionally substituted cycloalkyl; or

  f) optionally substituted heterocyclyl; And

R ₁ , R ₂ , R ₄ , R ₅ , and R ₈ are as defined herein.

Another aspect is a compound of formula (XVI), or a salt, solvate, hydrate or prodrug thereof, wherein:

,

,

,

,

, 또는

이고;Each R < ₃₅ >

,

,

,

,

, or

ego;

Each X is independently O or S;

Each Y is independently OH, NH _2, or NH-SO ₂ -R _17, and;

Each n is independently 1, 2, or 3;

Each o is independently 0, 1, 2, or 3;

Each p is independently 0, 1, 2, or 3;

Each t is independently 0, 1, 2, or 3;

Each R < ₁₄ > is independently:

,

,

,

,

,

,또는

로 치환된 알킬; a) one, two or three OH, haloalkoxy, optionally substituted heterocyclo, optionally substituted heteroaryl,

,

,

,

,

,

,or

≪ / RTI >

로 치환된 알콕시;b) 0, 1, 2, or 3 independent OR ₁₇ or

≪ / RTI >

; 또는c)

; or

   d) optionally substituted heterocyclo;

Each R ₃₂ is independently:

   a) haloalkyl;

   b) halo;

,

,

,

,

, 또는

로 치환된 알킬; 또는 c) 0, 1, 2, or 3 independent OH, haloalkoxy, optionally substituted heterocyclo, optionally substituted heteroaryl,

,

,

,

,

, or

≪ / RTI > or

이고;d)

ego;

Each R < ₁₆ > is independently:

   a) 0, 1, 2, or 3 independently substituted aralkyl:

      (1) cyano;

      (2) halo;

;(3)

;

      (4) alkoxy;

      (5) haloalkyl;

      (6) haloalkoxy;

      (7) optionally substituted alkyl;

      (8) optionally substituted aryl;

      (9) optionally substituted heteroaryl; or

      (10) optionally substituted heterocyclyl;

b) OR ₁₇ ; or

   c) optionally substituted aryl;

이다.Each R < ₁₇ > is independently H, optionally substituted alkyl, haloalkyl, or

to be.

Each R < ₁₈ > is independently:

   a) 0, 1, 2, or 3 independently substituted aryl

      (1) halo;

      (2) haloalkyl;

      (3) alkoxy;

      (4) haloalkoxy;

      (5) optionally substituted cycloalkyl;

      (6) optionally substituted heterocyclyl

      (7) optionally substituted alkyl

;(8)

;

(9) OR ₁₉ ;

(10) SR ₁₉ ;

      (11) optionally substituted heteroaryl; or

      (12) cyano;

   b) optionally substituted cycloalkyl;

   c) optionally substituted heteroaryl;

   d) optionally substituted heterocyclyl;

   e) optionally substituted alkyl;

   f) optionally substituted cycloalkylalkyl;

   g) optionally substituted cycloalkylalkoxy;

   h) haloalkyl;

   i) haloalkoxy;

   j) haloalkoxyalkyl;

; 또는k)

; or

   l) an optionally substituted aralkyl;

Each R < ₁₉ > is independently H, optionally substituted alkyl, or haloalkyl;

이고;Each R < ₂₀ > is independently H, optionally substituted alkyl, or

ego;

이고;Each R ₃₃ is independently H, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkylcarbonyl, or

ego;

Each R < ₂₂ > is independently:

;a)

;

   b) optionally substituted alkyl;

   c) optionally substituted aryl;

   d) optionally substituted heteroaryl;

   e) optionally substituted cycloalkyl; or

   f) optionally substituted heterocyclyl;

이고; 및Each R < ₂₅ > is independently optionally substituted aryl; Optionally substituted arylalkyl, haloalkoxy, (haloalkoxy) alkyl, cycloalkyl, _{alkyl, -CH 2 CF 2 CF 3,} -CF 2 CF 3, or

ego; And

R ₁ , R ₂ , R ₄ , R ₅ , and R ₈ are as defined herein.

Another aspect is a compound of formula (VII), or a salt, solvate, hydrate or prodrug thereof, wherein:

R < ₁ > is halo (e.g., fluorine);

R < ₂ > is halo (e.g., fluorine);

Each R ₂₇ is independently alkyl, cycloalkyl, or aralkyl each of which is substituted with 0, 1, 2 or 3, independent R ₈ ;

R ₅ is H, alkyl, phosphato, phosphito, alkoxy phosphato, or -C (O) alkyl optionally substituted with 1 or 2 amino;

Each R < ₈ > is independently optionally substituted alkyl, cyano, haloalkyl, alkoxy, halo, or haloalkoxy;

,

,

,

,

, 또는

이고;Each R < ₃₀ >

,

,

,

,

, or

ego;

Each X is independently O or S;

Each Y is independently OH, NH _2, or NH-SO ₂ -R _17, and;

Each n is independently 0, 1, 2, or 3;

Each o is independently 0, 1, 2, or 3;

Each t is independently 0, 1, 2, or 3;

Each R < ₃₁ > is independently:

,

,

,

,

,

, 또는

로 치환된 알킬;a) 1, 2, or 3 independent OH, haloalkoxy, optionally substituted heterocyclo, optionally substituted heteroaryl,

,

,

,

,

,

, or

≪ / RTI >

로 치환된 알콕시;b) an independent OR ₁₇ of 0, 1, 2, or 3; or

≪ / RTI >

;c)

;

   d) halo;

   e) haloalkyl;

   f) haloalkoxy; or

   g) optionally substituted heterocyclo;

Each R ₃₂ is independently:

   a) haloalkyl;

   b) halo;

,

,

,

,

, 또는

로 치환된 알킬; 또는c) 0, 1, 2, or 3 independent OH, haloalkoxy, optionally substituted heterocyclo, optionally substituted heteroaryl,

,

,

,

,

, or

≪ / RTI > or

;또는 d)

;or

   e) haloalkoxy;

Each R < ₁₆ > is independently:

   a) 0, 1, 2, or 3 independently substituted aralkyl:

      (1) cyano;

      (2) halo;

;(3)

;

      (4) alkoxy;

      (5) haloalkyl;

      (6) haloalkoxy;

      (7) optionally substituted alkyl;

      (8) optionally substituted aryl;

      (9) optionally substituted heteroaryl; or

      (10) optionally substituted heterocyclyl;

b) OR ₁₇ ; or

   c) optionally substituted aryl;

이고;Each R < ₁₇ > is independently H, optionally substituted alkyl, haloalkyl, or

ego;

Each R < ₁₈ > is independently:

   a) 0, 1, 2, or 3 independently substituted aryl;

      (1) halo;

      (2) haloalkyl;

      (3) alkoxy;

      (4) haloalkoxy;

      (5) optionally substituted cycloalkyl;

      (6) optionally substituted heterocyclyl;

      (7) optionally substituted alkyl;

;(8)

;

(9) OR ₁₉ ;

(10) SR ₁₉ ;

      (11) optionally substituted heteroaryl; or

      (12) cyano;

   b) optionally substituted cycloalkyl;

   c) optionally substituted heteroaryl;

   d) optionally substituted heterocyclyl;

   e) optionally substituted alkyl;

   f) optionally substituted cycloalkylalkyl;

   g) optionally substituted cycloalkylalkoxy;

   h) haloalkyl;

   i) haloalkoxy;

   j) haloalkoxyalkyl;

; 또는k)

; or

   l) an optionally substituted aralkyl;

Each R < ₁₉ > is independently H, optionally substituted alkyl, or haloalkyl;

이고;Each R < ₂₀ > is independently H, optionally substituted alkyl, haloalkyl, or

ego;

이고;Each R < ₃₃ > is independently H, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkylcarbonyl, or

ego;

Each R < ₂₂ > is independently:

;a)

;

   b) optionally substituted alkyl;

   c) optionally substituted aryl;

   d) optionally substituted heteroaryl;

   e) optionally substituted cycloalkyl; or

   f) optionally substituted heterocyclyl; And

이다.bracket R < ₂₅ > is independently optionally substituted aryl; Optionally substituted arylalkyl, haloalkoxy, (haloalkoxy) alkyl, cycloalkyl, _{alkyl, -CH 2 CF 2 CF 3,} -CF 2 CF 3, or

to be.

Another aspect is a compound of formula (III), or a salt, solvate, hydrate or prodrug thereof, wherein:

R ₅ is H, alkyl, phosphato, phosphito, alkoxy phosphato, or -C (O) alkyl optionally substituted with 1 or 2 amino;

,

,

,

, 또는

이고;Each R < ₁₃ > Each R < ₁₃ >

,

,

,

, or

ego;

Each X is independently O or S;

Each n is independently 0, 1, 2, or 3;

Each o is independently 0, 1, 2, or 3;

Each p is independently 0, 1, 2, or 3;

Each t is independently 0, 1, 2, or 3;

Each R < ₁₄ > is independently:

,

,

,

,

,

, 또는

로 치환된 알킬; a) 1, 2, or 3 independent OH, haloalkoxy, optionally substituted heterocyclo, optionally substituted heteroaryl,

,

,

,

,

,

, or

≪ / RTI >

로 치환된 알콕시;b) an independent OR ₁₇ of 0, 1, 2, or 3; or

≪ / RTI >

;c)

;

Each R < ₁₅ > is independently:

   a) haloalkyl;

   b) halo;

,

,

,

,

, 또는

로 치환된 알킬; c) 0, 1, 2, or 3 independent OH, haloalkoxy, optionally substituted heterocyclo, optionally substituted heteroaryl,

,

,

,

,

, or

≪ / RTI >

이고;d)

ego;

Each R < ₁₆ > is independently:

   a) 0, 1, 2, or 3 independently substituted aralkyl:

      (1) cyano;

      (2) halo;

;(3)

;

      (4) alkoxy;

      (5) haloalkyl;

      (6) haloalkoxy;

      (7) optionally substituted alkyl;

      (8) optionally substituted aryl;

      (9) optionally substituted heteroaryl; or

      (10) optionally substituted heterocyclyl;

b) OR ₁₇ ; or

   c) optionally substituted aryl;

이다.Each R < ₁₇ > is independently H, optionally substituted alkyl, haloalkyl, or

to be.

Each R < ₁₈ > is independently:

   a) independently substituted 0, 1, 2, or 3 aryl:

      (1) halo;

      (2) haloalkyl;

      (3) alkoxy;

      (4) haloalkoxy;

      (5) optionally substituted cycloalkyl;

      (6) optionally substituted heterocyclyl;

      (7) optionally substituted alkyl;

;(8)

;

(9) OR ₁₉ ;

(10) SR ₁₉ ;

      (11) optionally substituted heteroaryl; or

      (12) cyano;

   b) optionally substituted cycloalkyl;

   c) optionally substituted heteroaryl;

   d) optionally substituted heterocyclyl;

   e) optionally substituted alkyl;

   f) optionally substituted cycloalkylalkyl;

   g) optionally substituted cycloalkylalkoxy;

   h) haloalkyl;

   i) haloalkoxy;

   j) haloalkoxyalkyl;

;또는k)

;or

   l) an optionally substituted aralkyl;

Each R < ₁₉ > is independently H, optionally substituted alkyl, or haloalkyl;

이고;Each R < ₂₀ > is independently H, optionally substituted alkyl, haloalkyl, or

ego;

이고; 및Each R _{21 is} independently H, optionally substituted heteroaryl, optionally substituted alkyl, haloalkyl, optionally substituted alkylcarbonyl, or

ego; And

Each R < ₂₂ > is independently:

;a)

;

   b) optionally substituted alkyl;

          c) optionally substituted aryl;

          d) optionally substituted heteroaryl;

          e) optionally substituted cycloalkyl;

   f) optionally substituted heterocyclyl.

Another aspect is a compound of formula (XII), or a salt, solvate, hydrate or prodrug thereof, wherein:

R ₅ is H, alkyl, phosphato, phosphito, alkoxy phosphato, or -C (O) alkyl optionally substituted with 1 or 2 amino;

,

,

,

,

, 또는

이고;Each R < ₃₅ >

,

,

,

,

, or

ego;

Each X is independently O or S;

Each Y is independently OH, NH _2, or NH-SO ₂ -R _17, and;

Each n is independently 1, 2, or 3;

Each o is independently 0, 1, 2, or 3;

Each p is independently 0, 1, 2, or 3;

Each t is independently 0, 1, 2, or 3;

Each R < ₁₄ > is independently:

,

,

,

,

,

, 또는

로 치환된 알킬;a) 1, 2, or 3 independent OH, haloalkoxy, optionally substituted heterocyclo, optionally substituted heteroaryl,

,

,

,

,

,

, or

≪ / RTI >

로 치환된 알콕시;b) an independent OR ₁₇ of 0, 1, 2, or 3; or

≪ / RTI >

; 또는c)

; or

   d) optionally substituted heterocyclo;

Each R ₃₂ is independently:

   a) haloalkyl;

   b) halo;

,

,

,

,

, 또는

로 치환된 알킬; 또는 c) 0, 1, 2, or 3 independent OH, haloalkoxy, optionally substituted heterocyclo, optionally substituted heteroaryl,

,

,

,

,

, or

≪ / RTI > or

; 또는d)

; or

   e) haloalkoxy;

Each R < ₁₆ > is independently:

   a) 0, 1, 2, or 3 independently substituted aralkyl:

      (1) cyano;

      (2) halo;

;(3)

;

      (4) alkoxy;

      (5) haloalkyl;

      (6) haloalkoxy;

      (7) optionally substituted alkyl;

      (8) optionally substituted aryl;

      (9) optionally substituted heteroaryl; or

      (10) optionally substituted heterocyclyl;

b) OR ₁₇ ; or

   c) optionally substituted aryl;

이고;Each R < ₁₇ > is independently H, optionally substituted alkyl, haloalkyl, or

ego;

Each R < ₁₈ > is independently:

   a) independently substituted 0, 1, 2, or 3 aryl:

      (1) halo;

      (2) haloalkyl;

      (3) alkoxy;

      (4) haloalkoxy;

      (5) optionally substituted cycloalkyl;

      (6) optionally substituted heterocyclyl;

      (7) optionally substituted alkyl;

;(8)

;

(9) OR ₁₉ ;

(10) SR ₁₉ ;

      (11) optionally substituted heteroaryl; or

      (12) cyano;

   b) optionally substituted cycloalkyl;

   c) optionally substituted heteroaryl;

   d) optionally substituted heterocyclyl;

   e) optionally substituted alkyl;

   f) optionally substituted cycloalkylalkyl;

   g) optionally substituted cycloalkoxy;

   h) haloalkyl;

   i) haloalkoxy;

   j) haloalkoxyalkyl;

; 또는 k)

; or

   l) an optionally substituted aralkyl;

Each R < ₁₉ > is independently H, optionally substituted alkyl or haloalkyl;

이고;Each R < ₂₀ > is independently H, optionally substituted alkyl, or

ego;

이고;Each R _{33 is} independently H, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkylcarbonyl, or

ego;

Each R < ₂₂ > is independently:

;a)

;

   b) optionally substituted alkyl;

   c) optionally substituted aryl;

   d) optionally substituted heteroaryl;

          e) optionally substituted cycloalkyl;

   f) optionally substituted heterocyclyl; And

이다.Each R < ₂₅ > is independently optionally substituted aryl; Optionally substituted arylalkyl, haloalkoxy, (haloalkoxy) alkyl, cycloalkyl, _{alkyl, -CH 2 CF 2 CF 3,} -CF 2 CF 3, or

to be.

Another aspect is a compound of formula (XIII), or a salt, solvate, hydrate or prodrug thereof, wherein:

R ₅ is H, alkyl, phosphato, phosphito, alkoxy phosphato, or -C (O) alkyl optionally substituted with 1 or 2 amino;

또는

이고;Each R < ₃₆ >

or

ego;

Each n is independently 1, 2, or 3;

Each p is independently 0, 1, 2, or 3;

Each R < ₃₇ > is independently halo, haloalkyl, or haloalkoxy;

Each R < ₃₈ > is independently:

,

,

,

,

,

, 또는

로 치환된 알킬이고;a) 1, 2, or 3 independent OH, haloalkoxy, optionally substituted heterocyclo, optionally substituted heteroaryl,

,

,

,

,

,

, or

≪ / RTI >

로 치환된 알콕시;b) an independent OR ₁₇ of 0, 1, 2, or 3; or

≪ / RTI >

; 또는c)

; or

   d) optionally substituted heterocyclo;

이고,Each R < ₁₇ > is independently H, optionally substituted alkyl, haloalkyl, or

ego,

Each R < ₁₉ > is independently H, optionally substituted alkyl or haloalkyl; And

이다.Each R _{33 is} independently H, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkylcarbonyl, or

to be.

In another aspect, n = 1. In another aspect, n = 2. In another aspect, n = 3.

Another aspect is a compound of formula (VIII), or a salt, solvate, hydrate or prodrug thereof, wherein:

Each R < ₄ > is independently aryl substituted with 0, 1, 2 or 3, independent R < ₈ >;

R ₅ is H, alkyl, phosphato, phosphito, alkoxy phosphato, or -C (O) alkyl optionally substituted with 1 or 2 amino;

Each R < ₇ > is independently H, optionally substituted alkyl, optionally substituted haloalkyl, or optionally substituted arylalkyl;

Each R < ₈ > is independently optionally substituted alkyl, cyano, haloalkyl, alkoxy, halo, or haloalkoxy;

또는

이고;Each R ₃₉ is independently

or

ego;

Each R ₂₉ is R ₂₈ , -C (O) R ₄ , -C (O) R ₇ , -SO ₂ R ₄ ;

Each R ₂₈ is independently aryl, alkyl, cycloalkyl, or aralkyl each of which is substituted with 0, 1, 2 or 3, independent R ₈ ;

,

,

,

,

, 또는

이고;Each R < ₃₅ >

,

,

,

,

, or

ego;

Each X is independently O or S;

Each Y is independently OH, NH _2, or NH-SO ₂ -R _17, and;

Each n is independently 0, 1, 2, or 3;

Each o is independently 0, 1, 2, or 3;

Each p is independently 0, 1, 2, or 3;

Each t is independently 0, 1, 2, or 3;

Each R < ₁₄ > is independently:

,

,

,

,

,

, 또는

로 치환된 알킬;a) 1, 2, or 3 independent OH, haloalkoxy, optionally substituted heterocyclo, optionally substituted heteroaryl,

,

,

,

,

,

, or

≪ / RTI >

로 치환된 알콕시;b) an independent OR ₁₇ of 0, 1, 2, or 3; or

≪ / RTI >

;c)

;

   d) optionally substituted heterocyclo;

Each R ₃₂ is independently:

   a) haloalkyl;

   b) halo;

,

,

,

,

, 또는

로 치환된 알킬; c) 0, 1, 2, or 3 independent OH, haloalkoxy, optionally substituted heterocyclo, optionally substituted heteroaryl,

,

,

,

,

, or

≪ / RTI >

; 또는 d)

; or

   e) haloalkoxy;

Each R < ₁₆ > is independently:

   a) 0, 1, 2, or 3 independently substituted aralkyl:

      (1) cyano;

      (2) halo;

;(3)

;

      (4) alkoxy;

      (5) haloalkyl;

      (6) haloalkoxy;

      (7) optionally substituted alkyl;

      (8) optionally substituted aryl;

      (9) optionally substituted heteroaryl; or

      (10) optionally substituted heterocyclyl;

b) OR ₁₇ ; or

   c) optionally substituted aryl;

이고;Each R < ₁₇ > is independently H, optionally substituted alkyl, haloalkyl, or

ego;

Each R < ₁₈ > is independently:

   a) 0, 1, 2 or 3 independently substituted aryl:

      (1) halo;

      (2) haloalkyl;

      (3) alkoxy;

      (4) haloalkoxy;

      (5) optionally substituted cycloalkyl;

      (6) optionally substituted heterocyclyl;

      (7) optionally substituted alkyl;

;(8)

;

(9) OR ₁₉ ;

(10) SR ₁₉ ;

      (11) optionally substituted heteroaryl; or

      (12) cyano;

   b) optionally substituted cycloalkyl;

   c) optionally substituted heteroaryl;

   d) optionally substituted heterocyclyl;

   e) optionally substituted alkyl;

   f) optionally substituted cycloalkylalkyl;

   g) optionally substituted cycloalkylalkoxy;

   h) haloalkyl;

   i) haloalkoxy;

   j) haloalkoxyalkyl;

이고;k)

ego;

   l) optionally substituted aralkyl

Each R < ₁₉ > is independently H, optionally substituted alkyl, or haloalkyl;

이고;Each R < ₂₀ > is independently H, optionally substituted alkyl, or

ego;

이고;Each R < ₃₃ > is independently H, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkylcarbonyl, or

ego;

Each R < ₂₂ > is independently:

;a)

;

   b) optionally substituted alkyl;

   c) optionally substituted aryl;

   d) optionally substituted heteroaryl;

   e) optionally substituted cycloalkyl; or

   f) optionally substituted heterocyclyl;

이다.Each R < ₂₅ > is independently optionally substituted aryl; Optionally substituted arylalkyl, haloalkoxy, (haloalkoxy) alkyl, cycloalkyl, _{alkyl, -CH 2 CF 2 CF 3,} -CF 2 CF 3, or

to be.

Another aspect is a compound of formula (XIV), or a salt, solvate, hydrate or prodrug thereof, wherein:

R ₅ is H, alkyl, phosphato, phosphito, alkoxy phosphato, or -C (O) alkyl optionally substituted with 1 or 2 amino;

또는

이고;Each R < ₃₆ >

or

ego;

Each n is independently 1, 2, or 3;

Each p is independently 0, 1, 2, or 3;

Each R < ₃₇ > is independently halo, haloalkyl, or haloalkoxy;

Each R < ₃₈ > is independently:

,

,

,

,

,

,또는

로 치환된 알킬; a) 1, 2, or 3 independent OH, haloalkoxy, optionally substituted heterocyclo, optionally substituted heteroaryl,

,

,

,

,

,

,or

≪ / RTI >

로 치환된 알콕시;b) 0, 1, 2, or 3 independent OR ₁₇ or

≪ / RTI >

; 또는c)

; or

   d) optionally substituted heterocyclo;

이고;Each R < ₁₇ > is independently H, optionally substituted aryl, haloalkyl, or

ego;

Each R < ₁₉ > is independently H, optionally substituted alkyl, or haloalkyl; And

이다.Each R < ₃₃ > is independently H, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkylcarbonyl, or

to be.

In another aspect, n = 1. In another aspect, n = 2. In another aspect, n = 3.

Another aspect is a compound of formula (IX), or a salt, solvate, hydrate or prodrug thereof, wherein:

Each R < ₄ > is independently aryl substituted with 0, 1, 2 or 3, independent R < ₈ >;

R ₅ is H, alkyl, phosphato, phosphito, alkoxy phosphato, or -C (O) alkyl optionally substituted with 1 or 2 amino;

Each R < ₇ > is independently H, optionally substituted alkyl, optionally substituted haloalkyl, or optionally substituted arylalkyl;

Each R < ₈ > is independently optionally substituted alkyl, cyano, haloalkyl, alkoxy, halo, or haloalkoxy;

또는

이고;Each R ₃₉ is independently

or

ego;

Each R ₂₉ is independently R ₂₈ , -C (O) R ₄ , -C (O) R ₇ , -SO ₂ R ₄ ;

Each R ₂₈ is independently aryl, alkyl, cycloalkyl, or aralkyl each of which is substituted with 0, 1, 2 or 3, independent R ₈ ;

,

,

,

,

, 또는

이고;Each R < ₃₅ >

,

,

,

,

, or

ego;

Each X is independently O or S;

Each Y is independently OH, NH _2, or NH-SO ₂ -R _17, and;

Each n is independently 1, 2, or 3;

Each o is independently 0, 1, 2, or 3;

Each p is independently 0, 1, 2, or 3;

Each t is independently 0, 1, 2, or 3;

Each R < ₁₄ > is independently:

,

,

,

,

,

, 또는

로 치환된 알킬이고;a) 1, 2, or 3 independent OH, haloalkoxy, optionally substituted heterocyclo, optionally substituted heteroaryl,

,

,

,

,

,

, or

≪ / RTI >

로 치환된 알콕시;b) 0, 1, 2, or 3 independent OR ₁₇ or

≪ / RTI >

; 또는c)

; or

   d) optionally substituted heterocyclo;

Each R ₃₂ is independently:

   a) haloalkyl;

   b) halo;

,

,

,

,

, 또는

로 치환된 알킬; c) 0, 1, 2, or 3 independent OH, haloalkoxy, optionally substituted heterocyclo, optionally substituted heteroaryl,

,

,

,

,

, or

≪ / RTI >

; 또는d)

; or

   e) haloalkoxy;

Each R < ₁₆ > is independently:

   a) 0, 1, 2, or 3 independently substituted aralkyl:

      (1) cyano;

      (2) halo;

;(3)

;

      (4) alkoxy;

      (5) haloalkyl;

      (6) haloalkoxy;

      (7) optionally substituted alkyl;

      (8) optionally substituted aryl;

      (9) optionally substituted heteroaryl; or

      (10) optionally substituted heterocyclyl;

b) OR ₁₇ ; or

   c) optionally substituted aryl;

이고, Each R < ₁₇ > is independently H, optionally substituted alkyl, haloalkyl, or

ego,

Each R < ₁₈ > is independently:

   a) independently substituted 0, 1, 2, or 3 aryl:

      (1) halo;

      (2) haloalkyl;

      (3) alkoxy;

      (4) haloalkoxy;

      (5) optionally substituted cycloalkyl;

      (6) optionally substituted heterocyclyl;

      (7) optionally substituted alkyl;

;(8)

;

(9) OR ₁₉ ;

(10) SR ₁₉ ;

       (11) optionally substituted heteroaryl; or

       (12) cyano;

   b) optionally substituted cycloalkyl;

   c) optionally substituted heteroaryl;

   d) optionally substituted heterocyclyl;

   e) optionally substituted alkyl;

   f) optionally substituted cycloalkylalkyl;

   g) optionally substituted cycloalkylalkoxy;

   h) haloalkyl;

   i) haloalkoxy;

   j) haloalkoxyalkyl;

; 또는k)

; or

   l) an optionally substituted aralkyl;

Each R < ₁₉ > is independently H, optionally substituted alkyl, or haloalkyl;

이고;Each R < ₂₀ > is independently H, optionally substituted alkyl, or

ego;

이고;Each R < ₃₃ > is independently H, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkylcarbonyl, or

ego;

Each R < ₂₂ > is independently:

;a)

;

   b) optionally substituted alkyl;

   c) optionally substituted aryl;

   d) optionally substituted heteroaryl;

   e) optionally substituted cycloalkyl; or

   f) optionally substituted heterocyclyl;

이다.Each R < ₂₅ > is independently optionally substituted aryl; Optionally substituted arylalkyl, haloalkoxy, (haloalkoxy) alkyl, cycloalkyl, _{alkyl, -CH 2 CF 2 CF 3,} -CF 2 CF 3, or

to be.

Another aspect is a compound of formula (XVII), or a salt, solvate, hydrate or prodrug thereof, wherein:

Each R < ₄ > is independently aryl substituted with 0, 1, 2 or 3, independent R < ₈ >;

Each R ₂₇ is independently alkyl, cycloalkyl, or aralkyl each of which is substituted with 0, 1, 2 or 3, independent R ₈ ;

R ₅ is H, alkyl, phosphato, phosphito, alkoxy phosphato, or -C (O) alkyl optionally substituted with 1 or 2 amino;

Each R < ₇ > is independently H, optionally substituted alkyl, optionally substituted haloalkyl, or optionally substituted arylalkyl;

Each R < ₈ > is independently optionally substituted alkyl, cyano, haloalkyl, alkoxy, halo, or haloalkoxy;

또는

이고;Each R < ₃₄ >

or

ego;

Each R ₂₉ is independently R ₂₈ , -C (O) R ₄ , -C (O) R ₇ , -SO ₂ R ₄ ;

Each R < ₂₈ > is independently aryl, alkyl, cycloalkyl, or aralkyl each independently substituted with 0, 1, 2, or 3 independent R < ₈ >;

,

,

,

,

, 또는

이고;Each R < ₃₀ >

,

,

,

,

, or

ego;

Each X is independently O or S;

Each Y is independently OH, NH _2, or NH-SO ₂ -R _17, and;

Each n is independently 0, 1, 2, or 3;

Each o is independently 0, 1, 2, or 3;

Each p is independently 0, 1, 2, or 3;

Each t is independently 0, 1, 2, or 3;

Each R < ₃₁ > is independently:

,

,

,

,

,

, 또는 로 치환된 알킬이고;a) 1, 2, or 3 independent OH, haloalkoxy, optionally substituted heterocyclo, optionally substituted heteroaryl,

,

,

,

,

,

, or ≪ / RTI >

로 치환된 알콕시;b) an independent OR ₁₇ of 0, 1, 2, or 3; or

≪ / RTI >

;c)

;

   d) halo;

   e) haloalkyl;

   f) haloalkoxy; or

   g) optionally substituted heterocyclo;

Each R ₃₂ is independently:

   a) haloalkyl;

   b) halo;

,

,

,

,

, 또는

로 치환된 알킬; c) 0, 1, 2, or 3 independent OH, haloalkoxy, optionally substituted heterocyclo, optionally substituted heteroaryl,

,

,

,

,

, or

≪ / RTI >

; 또는d)

; or

   e) haloalkoxy;

Each R < ₁₆ > is independently:

   a) 0, 1, 2, or 3 independently substituted aralkyl:

      (1) cyano;

      (2) halo;

;(3)

;

      (4) alkoxy;

      (5) haloalkyl;

      (6) haloalkoxy;

      (7) optionally substituted alkyl;

      (8) optionally substituted aryl;

      (9) optionally substituted heteroaryl; or

      (10) optionally substituted heterocyclyl;

b) OR ₁₇ ; or

   c) optionally substituted aryl;

이고, Each R < ₁₇ > is independently H, optionally substituted alkyl, haloalkyl, or

ego,

Each R < ₁₈ > is independently:

   a) independently substituted 0, 1, 2, or 3 aryl:

      (1) halo;

      (2) haloalkyl;

      (3) alkoxy;

      (4) haloalkoxy;

      (5) optionally substituted cycloalkyl;

      (6) optionally substituted heterocyclyl;

      (7) optionally substituted alkyl;

;(8)

;

(9) OR ₁₉ ;

(10) SR ₁₉ ;

      (11) optionally substituted heteroaryl; or

      (12) cyano;

   b) optionally substituted cycloalkyl;

   c) optionally substituted heteroaryl;

   d) optionally substituted heterocyclyl;

   e) optionally substituted alkyl;

   f) optionally substituted cycloalkylalkyl;

   g) optionally substituted cycloalkylalkoxy;

   h) haloalkyl;

   i) haloalkoxy;

   j) haloalkoxyalkyl;

; 또는k)

; or

   l) an optionally substituted aralkyl;

Each R < ₁₉ > is independently H, optionally substituted alkyl, or haloalkyl;

이고;Each R < ₂₀ > is independently H, optionally substituted alkyl, haloalkyl, or

ego;

이고;Each R < ₃₃ > is independently H, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkylcarbonyl, or

ego;

Each R < ₂₂ > is independently:

;a)

;

   b) optionally substituted alkyl;

   c) optionally substituted aryl;

    d) optionally substituted heteroaryl;

    e) optionally substituted cycloalkyl; or

    f) optionally substituted heterocyclyl;

이다.Each R < ₂₅ > is independently optionally substituted aryl; Optionally substituted arylalkyl, haloalkoxy, (haloalkoxy) alkyl, cycloalkyl, _{alkyl, -CH 2 CF 2 CF 3,} -CF 2 CF 3, or

to be.

Another aspect is a compound of formula (XVII), or a salt, solvate, hydrate or prodrug thereof, wherein:

Each R < ₄ > is independently aryl substituted with 0, 1, 2 or 3, independent R < ₈ >;

R ₅ is H, alkyl, phosphato, phosphito, alkoxy phosphato, or -C (O) alkyl optionally substituted with 1 or 2 amino;

Each R < ₈ > is independently optionally substituted alkyl, cyano, haloalkyl, alkoxy, halo, or haloalkoxy;

또는

이고;Each R < ₃₆ >

or

ego;

Each n is independently 1, 2, or 3;

Each p is independently 0, 1, 2, or 3;

Each R < ₃₇ > is independently halo, haloalkyl, or haloalkoxy;

Each R < ₃₈ > is independently:

,

,

,

,

,

,또는

로 치환된 알킬; a) 1, 2, or 3 independent OH, haloalkoxy, optionally substituted heterocyclo, optionally substituted heteroaryl,

,

,

,

,

,

,or

≪ / RTI >

로 치환된 알콕시;b) 0, 1, 2, or 3 independent OR ₁₇ or

≪ / RTI >

; 또는c)

; or

   d) optionally substituted heterocyclo;

이고;Each R < ₁₇ > is independently H, optionally substituted alkyl, haloalkyl, or

ego;

Each R < ₁₉ > is independently H, optionally substituted alkyl, or haloalkyl;

이다.Each R ₃₃ is independently H, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkylcarbonyl, or

to be.

In another aspect, n = 1. In another aspect, n = 2. In another aspect, n = 3.

Another aspect is a compound of formula of the present invention wherein n is 1 and R ₁₃ is in the 4-position of the phenyl ring in formula III.

Another aspect is a compound of formula of the present invention, wherein n is 1 and R ₁₃ is in the 3-position of the phenyl ring in formula III.

Another aspect is a compound of formula of the invention, wherein R < ₁ > is fluorine.

Another aspect is a compound of formula of the present invention, wherein R < ₂ > is fluorine.

Another aspect is a compound of formula of the present invention, wherein R ₁ and R ₂ are fluorine.

Another aspect is a compound of formula of the invention, wherein R < ₄ > is phenyl substituted with 0, 1, 2 or 3 independent R < ₈ >

Another aspect is a compound of formula of the invention, wherein R < ₄ > is phenyl substituted by 0, 1, 2 or 3 independent halos.

Another aspect is a compound of formula of the invention, wherein R < ₄ > is phenyl substituted by 0, 1, 2 or 3 independent fluorines.

Another aspect is a compound of formula of the invention, wherein R < ₄ > is 2,4-difluorophenyl.

Another aspect is a compound of formula of the present invention, wherein R < ₅ >

Another aspect is a compound of formula of the invention, wherein R < ₅ > is an amino substituted acyl.

Another aspect is a compound of formula of the invention, wherein R < ₅ > is -C (O) alkyl optionally substituted by one or two amino.

Another aspect is a compound of formula of the present invention, wherein R < ₅ > is phosphato.

Another aspect is a compound of formula of the invention, wherein:

R < ₁ > is fluorine;

R ₂ is fluorine;

R ₄ is 2,4-difluoro phenyl;

R < ₅ > is H;

이고; 및Ar ₂ is

ego; And

MBG is 1-tetrazolyl;

Another aspect is a compound of formula of the invention, wherein:

R < ₁ > is fluorine;

R ₂ is fluorine;

R ₄ is 2,4-difluoro phenyl;

R < ₅ > is H;

이고;Ar ₂ is

ego;

MBG is 1-tetrazolyl;

Each R < ₁₀ > is independently H, optionally substituted alkyl, optionally aryl, optionally substituted heterocycloalkyl, or optionally substituted arylalkyl;

R ₁₁ is phenyl, thienyl, arylalkyl, aryloxyalkyl each substituted with 0, 1, 2, or 3 independent R ₃ ;

Each R ₃ is independently selected from the group consisting of cyano, haloalkyl, halo, haloalkoxy, optionally substituted arylalkoxy, haloalkylaminocarbonyl, optionally substituted arylalkylaminocarbonyl, optionally substituted alkyl, -C ) R < _{10 &} gt ;; And

n is 1 or 2;

Another aspect is a compound of formula of the invention, wherein:

R < ₁ > is fluorine;

R ₂ is fluorine;

R ₄ is 2,4-difluoro phenyl;

R < ₅ > is H;

이고;Ar ₂ is

ego;

MBG is 1-tetrazolyl;

R ₁₁ is phenyl each of which is substituted with 0, 1, 2, or 3 independent R ₃ ;

Each R ₃ is independently selected from the group consisting of cyano, haloalkyl, halo, haloalkoxy, optionally substituted arylalkoxy, haloalkylaminocarbonyl, optionally substituted arylalkylaminocarbonyl, optionally substituted alkyl, -C ) R < _{10 &} gt ;; And

n is 1 or 2;

Another aspect is a compound of formula of the invention, wherein:

R < ₁ > is fluorine;

R ₂ is fluorine;

R ₄ is 2,4-difluoro phenyl;

R ₅ is H.

Another aspect is a compound of formula of the invention, wherein:

Each R ₃ is independently selected from the group consisting of cyano, haloalkyl, halo, haloalkoxy, optionally substituted arylalkoxy, haloalkylaminocarbonyl, optionally substituted arylalkylaminocarbonyl, optionally substituted alkyl, -C ) R < _{10 &} gt ;; And

n is 1 or 2;

Another aspect is a compound of formula of the invention, wherein:

Each R ₃ is independently selected from the group consisting of cyano, haloalkyl, halo, haloalkoxy, optionally substituted arylalkoxy, haloalkylaminocarbonyl, optionally substituted arylalkylaminocarbonyl, optionally substituted alkyl, -C ) R < _{10 &} gt ;; And

n is 1.

Another aspect is a compound of formula of the invention, wherein:

Each R ₃ is independently selected from the group consisting of cyano, haloalkyl, halo, haloalkoxy, optionally substituted arylalkoxy, haloalkylaminocarbonyl, optionally substituted arylalkylaminocarbonyl, optionally substituted alkyl, -C ) R < _{10 &} gt ;; And

n is 2.

Another aspect is a compound of formula of the invention, wherein:

Each arylalkoxy is optionally substituted with one or more substituents independently selected from the group consisting of halo, cyano, haloalkyl, haloalkoxy, alkylaminocarbonyl, heteroaryl, aminoalkyl, (Hydroxyalkyl), (haloalkoxy) alkyl, (di) alkylaminoalkyl, heteroarylalkyl, (haloalkyl) aminoalkyl (haloalkyl) aminoalkyl, (carboxyalkyl) aminoalkyl, (heterocyclyl) alkyl, heteroarylaminoalkyl, hydroxy (haloalkyl), (Cyanoalkylamino) alkyl, cyanoalkoxyalkyl, (cyanoalkylamino) alkyl, hydroxy (haloalkyl) aminoalkyl, (hydroxyalkylamino) alkyl ), (Heteroarylalkylamino) alkyl, or aryl. And the like.

Another aspect is a compound of formula of the invention, wherein:

Each aryloxyalkyl may be optionally substituted with halo, cyano, haloalkyl, haloalkoxy, or aryl.

Another aspect is a compound of formula of the invention, wherein:

Each arylalkylthio may be optionally substituted with halo, haloalkyl, haloalkoxy, or cyano.

Another aspect is a compound of formula of the invention, wherein:

Each arylalkylsulfonyl may be optionally substituted with halo, haloalkyl, haloalkoxy, or cyano.

Another aspect is a compound of formula of the invention, wherein:

Each arylalkylsulfinyl may be optionally substituted with halo, haloalkyl, haloalkoxy, or cyano.

Another aspect is a compound of formula of the invention, wherein:

Each heteroarylalkoxy can be optionally substituted with halo, haloalkyl, haloalkoxy, [(di) alkylamino] alkyl, heteroarylalkyl, or cyano.

Another aspect is a compound of formula of the invention, wherein:

Each arylthioalkyl may be optionally substituted with halo, haloalkyl, haloalkoxy, or cyano.

Another aspect is a compound of formula of the invention, wherein:

Each thienyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, haloalkyl, alkyl, haloalkylcarbonyl, haloalkylaminocarbonyl, haloarylalkylaminocarbonyl, cyanoarylalkylaminocarbonyl, haloalkylarylalkylaminocarbonyl, heterocyclo Alkylcarbonyl, methylsulfonyl-phenylalkylaminocarbonyl, or cyano. The term " alkyl "

Another aspect is a compound of formula of the invention, wherein:

Each arylalkylcarbonyl can be optionally substituted with cyano, halo, [(di) alkylamino] alkyl, haloalkyl, or haloalkoxy.

Another aspect is a compound of formula (IV), or a salt, solvate, hydrate or prodrug thereof, wherein:

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , and R ₁₀ are defined as described in the above examples.

Ar is aryl or heteroaryl;

n is 0, 1, 2 or 3;

Another aspect is a compound of formula of the invention, wherein:

Each R ₁₄ or R ₃₁ is independently selected from the group consisting of aminomethyl, hydroxymethyl, (2,2,2-trifluoroethyl) oxymethyl, (N N-dimethylamino) methyl, (acetamido) methyl, (1-pyrazolyl) methyl, (2, 2,2-trifluoroethyl) aminomethyl, (2-hydroxyethyl) oxy, (carboxymethyl) oxy, (2-hydroxyethyl) oxy, , (Carboxymethyl) aminomethyl, (ethylamino) methyl, (methylamino) methyl, (1-pyrrolidinyl) pyrrolidinyl) methyl, (2-oxazolyl) aminomethyl, 1-hydroxyethyl, (1-hydroxy) -2,2,2-trifluoroethyl 1-hydroxy-2,2,2-trifluoroethyl, (2,2-difluoroethyl) oxymethyl, (cyanomethyl) oxymethyl ((c pyrazolyl) methyl, (3-chloro-1H-pyrazolyl) methyl ((3-chloro-1H-pyrazolyl) 4-fluoro-1H-pyrazolyl) methyl), (4-chloro-1H-pyrazolyl) ), (4- (2-methoxyethyl) pyrazolyl) methyl, (3- (acetamidomethyl) pyrazolyl) methyl ((3- (acetamidomethyl) pyrazolyl) methyl), (4- (2-ethan-2-ol) pyrazolyl) Pyrazolyl) methyl, (2- (4-carboxy-lH-pyrazolyl) methyl) 2-oxazolyl-N-methylamino) methyl, (cyanomethyl-N-methyl (2-oxazolyl) Methyl) amino] methyl ([(2,2,2-trifluoroethyl) -N-me [(2,2-difluoro-2-hydroxyethyl) -N-methylamino] methyl], [(2,2-difluoro-2-hydroxyethyl) 2-hydroxyethyl] -N-methylamino), [(2-methyl-2-hydroxyethyl) - [(1-formyl-imidazol-2-yl) methyl] aminomethyl [(2-methyl- 2-yl) methyl] aminomethyl), [(1-formyl-imidazol-2-yl) methyl] Imidazol-1-yl) methyl, (2-methylaminocarbonyl-imidazol-1-yl) -yl) methyl), (4-methylpiperazin-1-yl) methyl, (4-formylpiperazin- 1-yl) (methyl), morpholinylmethyl, 1- (imidazolidin-2-onyl) methyl, 3- 2,5-dionyl) methyl, 1- (1-pyrazolyl) ethyl, 4 - [( (4 - [(S) -1- (2-methylpentan-3-yl) (2-hydroxy-1- (1-pyrazolyl) methyl) ) ethyl, 2-hydroxy-1- (dimethylamino) ethyl, or (cyanomethyl) aminomethyl.

Another aspect is a compound of formula of the invention, wherein:

Each R ₁₅ or R ₃₂ is independently trifluoromethyl, fluoro, or (dimethylamino) methyl.

Another aspect is a compound of formula of the invention, wherein:

Each R ₁₆ is independently selected from the group consisting of (4-cyanophenyl) methyl, (3-fluoro-4-cyanophenyl) methyl, ) Phenyl] methyl.

Another aspect is a compound of formula of the invention, wherein:

Each R ₁₇ , R ₁₈ , R ₁₉ , R ₂₀ , R ₃₃ and R ₂₁ are independently selected from the group consisting of H, 2,2,2-trifluoroethyl, methyl, acetyl, carboxymethyl, Fluorophenyl, 4- (difluoromethyl) pheny, 4- (dimethylaminomethyl) phenyl, cyanomethyl, 2-hydroxy-2,2-difluoroethyl, Hydroxy-2, 2-dimethylethyl, 2-hydroxy-2-methylethyl, (1-formyl-imidazol-2-yl) methyl or 2-oxazolyl.

In one aspect, any one of the formulas of the present invention (e. G., Formula I-XYII) inhibits (or is found to inhibit) lanosterol demethylase (CYP51).

In one aspect, it has been shown that any one of the formulas of the invention (e. G., Formula I-XYII) has an activity range for the target enzyme (see, for example, C. albicans MIC ≪ 1.0 μg / mL and A. fumigatus MIC ≤ 64 μg / mL).

The compounds of the present invention include those compounds that have been identified as having formed at least one of the following chemical interactions or bonds of metals to attain affinity for metal enzymes: sigma bonds, covalent bonds, coordination covalent bonds , Ionic bonds, pi bonds, delta bonds, or backbonding interactions. The compounds can also achieve affinity through weak interactions with metals such as van der Waals interactions, pie cation interactions, pi-anion interactions, dipole-dipole interactions, and ion-dipole interactions. In one aspect, the compound is identified as having a bonding interaction with the metal through a 1-tetrazolyl moiety; In another aspect, the compound is identified as having a mutual bond with the metal through the N2 of the 1-tetrazolyl moiety; In another aspect, the compound is identified as having a mutual bond with the metal through the N3 of the 1-tetrazolyl moiety; In another aspect, the compound is identified as having a mutual bond with the metal through the N4 of the 1-tetrazolyl moiety. In one aspect, the compound is identified as having a mutual bond with the metal through the 2-tetrazolyl moiety; In another aspect, the compound is identified as having a mutual bond with the metal through N1 of the 2-tetrazolyl moiety; In another aspect, the compound is identified as having a mutual bond with the metal through the N3 of the 2-tetrazolyl moiety; In another aspect, the compound is identified as having a mutual bond with the metal through the N4 of the 2-tetrazolyl moiety.

Methods for assessing metal-ligand interconnection are described, for example, in "Principles of Bioinorganic Chemistry" by Lippard and Berg, University Science Books, (1994); "Mechanisms of Inorganic Reactions" by Basolo and Pearson John Wiley & Sons Inc; 2nd edition (September 1967); "Biological Inorganic Chemistry" by Ivano Bertini, Harry Gray, Ed Stiefel, Joan Valentine, University Science Books (2007); Xue et al. "Nature Chemical Biology ", vol. 4, no. 2, 107-109 (2008), all of which are well known in the art.

In any case, the compounds of the present invention are selected from any one of the above formulas (e.g., Formula I-XVII) (and pharmaceutically acceptable salts, solvates, or hydrates thereof)

(4- (2- (4 - ((6- (2- (2,4-difluorophenyl) -1,1-difluoro-2- Ethynyl) phenyl) -2-oxoethyl) benzonitrile (4- (2- (4- (6- (2- (2,4- difluorophenyl) -1,1-difluoro -2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3-yl) ethynyl) phenyl) -2-oxoethyl) benzonitrile) (1);

Hydroxy-3- (lH-tetrazol-l-yl) propyl) pyridine-l- 3-yl) ethynyl) benzylamino) benzonitrile (4- (4 - ((6- (2- (2,4- difluorophenyl) -1,1- difluoro-2- -1-yl) propyl) pyridin-3-yl) ethynyl) benzylamino) benzonitrile) (2);

1- (5 - ((4 - ((2,2,2-tri < / RTI > (2,4-difluorophenyl) -1,1-difluoro-3- (1H-tetrazol-1-yl) -1- (5 - ((4 - ((2,2,2-trifluoroethylamino) methyl) phenyl) ethynyl) pyridin-2-yl) propan-2-ol) (3);

Ethynyl) pyridin-2-yl) -2- (2,4-difluorophenyl) -1,1-difluoro- 2-yl) -2- (2-pyrrolidin-1-yl) propan- , 4-difluorophenyl) -1,1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol) (4);

1- (5 - ((4 - ((5- (trifluoromethyl) -1H-pyrazol- (2,4-difluorophenyl) -1,1-difluoro-3- (lH-tetrazol-2-yl) methoxy) phenyl) ethynyl) 1-yl) -1- (5 - ((4 - ((5- (trifluoromethyl) thiophen-2-yl) methoxyphenyl) ethynyl) pyridin-2-yl) propan-2-ol) (5);

2- (2,4-difluorophenyl) -1,1-difluoro-1- (5 - ((4- ( 2- (2,4-difluorophenyl) -1,1-difluoro-1- (5 - ((4 - (( 5-fluorothiophen-2-yl) methoxy) phenyl) ethynyl) pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol) (6);

Ethynyl) pyridin-2-yl) -2- (2,4-difluorophenyl) -1,1-difluoro- Pyridin-2-yl) -2- (2 - ((4-chlorophenylamino) methyl) phenyl) ethynyl) pyridin- , 4-difluorophenyl) -1,1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol) (7);

2- (2,4-difluorophenyl) -1,1-difluoro-1- (5 - ((4- (4-fluorophenylamino) methyl) phenyl) ethynyl) pyridin- 2- (2,4-difluorophenyl) -1,1-difluoro-1- (5 - ((4 - ((4-fluorophenylamino) methyl) phenyl) ethynyl) pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol) (8);

2- (2,4-difluorophenyl) -1,1-difluoro-1- (5 - ((4- (4- (hydroxymethyl) benzyloxy) phenyl) ethynyl) pyridin- 2- (2,4-difluorophenyl) -1,1-difluoro-1- (5 - ((4- (4- (hydroxymethyl) benzyloxy) phenyl) ethynyl) pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol) (9);

1- (5 - ((4- (4 - ((2,2,2-trifluoroethoxy) phenyl) -1,1-difluoro- 2- (2,4-difluorophenyl) -1,1-difluoro-3- (1H-pyrazol- pyridin-2-yl) propan-2-ol) (prepared from (4- (4- 10);

2- (2,4-difluorophenyl) -1- (5 - ((4- (4- (dimethylamino) methyl) benzyloxy) phenyl) ethynyl) pyridin- 2- (2,4-difluorophenyl) -1- (5 - ((4- (4 - ((dimethylamino) methyl) benzyloxy phenyl) ethynyl) pyridin-2-yl) -1,1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol) (11);

Hydroxy-3- (1H-tetrazol-1-yl) -1H-pyrazole-3- (4 - ((6- (2- (2,4-difluorophenyl) -1,1-difluoro -2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3-yl) ethynyl) phenoxy) methyl) benzyl) acetamide) (12);

Ethynyl) pyridin-2-yl) -2- (2,4-difluoro-phenyl) ) -1,1-difluoro-3- (1H-tetrazol-1-yl) propan- yl) propan-2-ol) (13) (1 H) ;

1- (5 - ((4- (4 - ((2,2,2-trifluoroethoxy) phenyl) -1,1-difluoro- (2,4-difluorophenyl) -1,1-difluoro-3- (lH-pyrrolo [2,3-d] pyrimidin- pyridin-2-yl) propan-2-ol) (prepared from (4- (4- 14);

Ethynyl) pyridin-2 (2-hydroxyphenyl) -1,1-difluoro-1- (5- (2,4-difluorophenyl) -1,1-difluoro-1- (5 - ((4- (4- (2-hydroxyethoxy) benzyloxy) phenyl) ethynyl) pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol) (15);

2- (4 - ((4 - ((6- (2- (2,4-difluorophenyl) -1,1-difluoro-2- (4 - ((6- (2- (2,4-difluorophenyl) -1,1-difluoro -2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3-yl) ethynyl) phenoxy) methyl) phenoxy) acetic acid (16);

(4- (2- (4 - ((6- (2- (2,4-difluorophenyl) -1,1-difluoro-2- (2- (4 - ((6- (2- (2,4-difluorophenyl) - 1, 2-dihydroxyphenyl) -2-oxoethyl) -2-fluorobenzonitrile , 1-difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3-ylethynyl) phenyl) -2-oxoethyl) -2-fluorobenzonitrile) (17);

Ethynyl) pyridin-2-yl) -2- (2,4-difluorophenyl) -1,1 (dimethylamino) Methyl) phenyl) ethynyl) pyridin-2-yl) propan-2-ol (1- (5 - ((4- (difluoromethyl) phenylamino) yl) -2- (2,4-difluorophenyl) -1,1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol) (18);

2- (4-chloro-3-fluorophenyl) -1- (4 - ((6- (2- (2,4-difluorophenyl) -1,1- difluoro-2- 3- (4-chloro-3-fluorophenyl) -1- (4 - ((6- (2- 2,4-difluorophenyl) -1,1-difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3-yl) ethynyl) phenyl) ethanone) (19);

2- (4 - ((4 - ((6- (2- (2,4-difluorophenyl) -1,1-difluoro-2- (4 - ((6- (2- (2,4-difluorophenyl) -1,1-difluoro -2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3-yl) ethynyl) phenoxy) methyl) benzylamino) acetic acid) (20);

2- (2,4-difluorophenyl) -1- (5 - ((4- (4 - ((ethylamino) methyl) benzyloxy) phenyl) ethynyl) pyridin- 2- (2,4-difluorophenyl) -1- (5 - ((4- (4 - ((ethylamino) methyl) benzyloxy phenyl) ethynyl) pyridin-2-yl) -1,1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol) (21);

(5 - ((4- (4 - ((methylamino) methyl) benzyloxy) phenyl) ethynyl) pyridin- 2- (2,4- difluorophenyl) -1,1-difluoro-1- (5 - ((4- (4- ( (methylamino) methyl) benzyloxy) phenyl) ethynyl) pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol) (22);

1- (5 - ((4- (4- (pyrrolidin-1-ylmethyl) benzyloxy) phenyl) ethynyl) pyridine 2- (2,4-difluorophenyl) -1,1-difluoro-1- (5 - ((4- ( 4- (pyrrolidin-1-ylmethyl) benzyloxy) phenyl) ethynyl) pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol) (23);

Synthesis of 2- (2,4-difluorophenyl) -1,1-difluoro-1- (5 - ((4- (4- ((oxazol- 2- ylamino) methyl) benzyloxy) phenyl) ethynyl (2,4-difluorophenyl) -1,1-difluoro-1- (5 - ((4-fluorophenyl) - (4 - ((oxazol-2-ylamino) methyl) benzyloxy) phenyl) ethynyl) pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol) (24);

2- (2,4-difluorophenyl) -1,1-difluoro-1- (5- (4- (4- (1-hydroxyethyl) benzyloxy) phenyl) ethynyl) 2- (2,4-difluorophenyl) -1,1-difluoro-1- (5 - ((4- (4- ( 1-hydroxyethyl) benzyloxy) phenyl) ethynyl) pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol) (25);

1- (5 - ((4- (4- (2,2,2-trifluoro-phenyl) -1,1-difluoro-3- 2- (2,4-difluorophenyl) -1,1-difluoro-3- (1H) -thiophene- pyridin-2-yl) propan-2-ol The title compound was prepared in a similar manner to that described in Example 1, Step 1, using 1- (5- (4- (4- (2,2,2- ) 26;

Yl) methoxy) phenyl) ethynyl) pyridin-2 (2S) -2 - [(4- 2- (2,4-difluorophenyl) -1- (5 - ((4 - (((1 H) -trifluorophenyl) -1- Pyridin-2-yl) -1,1-difluoro-3- (1H-tetrazol-1-yl) propan- (27);

Hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridine-1-carboxylic acid 2- (4 - ((dimethylamino) methyl) phenyl) ethanone (1- (4- (6- (2- (2,4- difluorophenyl) -1,1 -difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3-yl) ethynyl) phenyl) -2- (4 - ((dimethylamino) methyl) phenyl) ethanone) (28);

2-yl) -2- (2,4-difluoroethoxy) methyl) benzyloxy) phenyl) ethynyl) pyridin- (1 - (5 - ((4- (4 - ((2,2-difluoroethoxy) methyl) benzyloxy) -1,1-difluoro-3- phenyl) ethynyl) pyridin-2-yl) -2- (2,4-difluorophenyl) -1,1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol) (29);

2- (4 - ((4 - ((6- (2- (2,4-difluorophenyl) -1,1-difluoro-2- Ethyl) phenoxy) methyl) benzyloxy) acetonitrile (2- (4 - ((4 - ((6- (2- (2,4- difluorophenyl) -1,1 -difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3-yl) ethynyl) phenoxy) methyl) benzyloxy) acetonitrile) (30);

Methyl) phenyl) ethynyl) pyridin-2-yl) -1- (5 - ((4 - ((dimethylamino) 2- (2,4-difluorophenyl) -1- (5 - ((4 - ((4 - ((dimethylamino) ) methyl) phenylamino) methyl) phenyl) ethynyl) pyridin-2-yl) -1,1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol) (31);

2- (4 - ((4 - ((6- (2- (2,4-difluorophenyl) -1,1-difluoro-2- Ethynyl) phenoxy) methyl) benzylamino) acetonitrile (2- (4 - ((4 - ((6- (2- (2,4- difluorophenyl) -1,1 -difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3-yl) ethynyl) phenoxy) methyl) benzylamino) acetonitrile) (32);

Hydroxy-3- (1H-tetrazol-1-yl) -1H-pyrazole-3- (4 - ((6- (2- (2,4-difluoro-phenyl) 1-difluorophenyl) -1,1-difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3- ylethynyl) phenoxy) methyl) benzyl) -1H-pyrazole- 33);

Ethynyl) pyridin-2-yl) -2- (2, 4-dihydroxyphenyl) (1 - (5 - ((4- (4 - ((3-chloro-1 H -trifluoromethyl- 2-yl) -2- (2,4-difluorophenyl) -1,1-difluoro-3- (1H-tetrazol-1-yl) methyl) benzyloxy) -2-ol) (34);

Ethynyl) pyridin-2-yl) -2- (2, 4-dihydroxyphenyl) (1 - (5 - ((4- (4 - ((4-chloro-1 H -trifluoromethylphenyl) -1,1-difluoro-3- 2-yl) -2- (2,4-difluorophenyl) -1,1-difluoro-3- (1H-tetrazol-1-yl) methyl) benzyloxy) -2-ol) (35);

Fluoro-1H-pyrazol-1-yl) methyl) benzyloxy) -1- (5 - ((4- (4- ) Phenyl) ethynyl) pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan- Pyridin-2-yl) -3- (1H-tetrazol-1-yl) methyl) benzyloxy) -2-ol) (36);

1- (5 - ((4- (4 - ((4- (2-methoxyethyl) -1 H-pyrazole-1- 2-yl) -3- (1H-tetrazol-1-yl) propan- yl) methyl) benzyloxy) phenyl) ethynyl) pyridin-2-yl) -3-piperidinecarboxylate [ (1H-tetrazol-1-yl) propan-2-ol) (37);

N - ((1- (4 - ((4- (6- (2- (2,4-difluorophenyl) -1,1- difluoro-2- Yl) ethyl) phenoxy) methyl) benzyl) -1H-pyrazol-3- yl) methyl) acetamide (N- ((6- (2- (2,4-difluorophenyl) -1,1-difluoro-2-hydroxy-3- (1H- tetrazol- 1- yl) propyl) pyridin- benzyl) -1H-pyrazol-3-yl) methyl) acetamide) (38);

1 -difluoro-1- (5 - ((4- (4 - ((4- (2-hydroxypropan- (2,4-difluorophenyl) pyridin-2-yl) -3- (1H-tetrazol-1 -yl) -1,1-difluoro-1- (5 - ((4- (4- (2-hydroxypropan-2-yl) -1H- pyrazol-1- yl) methyl) benzyloxy) phenyl) ethynyl) pyridine -2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol) (39);

1- (5 - ((4- (4 - ((4- (1 -hydroxyethyl) -1H-pyrazole-1- 2-yl) -3- (1H-tetrazol-1-yl) propan- yl) methyl) benzyloxy) phenyl) ethynyl) pyridin-2-yl) -3-piperidinone [ (1H-tetrazol-1-yl) propan-2-ol) (40);

Hydroxy-3- (1H-tetrazol-1-yl) -1H-pyrazole-3- Benzyl) -1H-pyrazole-4-carboxylic acid (1- (4 - {(4 - {[6- (2- (2,4- difluorophenyl) Yl) ethynyl) phenoxy) methyl) benzyl) -1H-pyrazole-4-carboxylic acid ( 41);

Methyl) benzyloxy) phenyl) -1,1-difluoro-1- (5 - ((4- (4- ( (2,4-difluorophenyl) -1,1-difluoro-1- (5-fluorophenyl) ((4- (4 - ((methyl (oxazol-2-yl) amino) methyl) benzyloxy) phenyl) ethynyl) pyridin- ) 42;

2 - ((4 - ((4 - ((6- (2- (2,4-difluorophenyl) -1,1-difluoro-2- (2 - ((4 - ((4 - ((6- (2- (2,4-difluorophenyl) 3-yl) ethynyl) phenoxy) methyl) benzyl) (methyl) amino) acetonitrile) (43) ;

Trifluoroethyl) amino] methyl} benzyl (2-methyl-2-oxoethyl) 2- (2,4-difluorophenyl) -1,1-difluoro-l- (2-hydroxyphenyl) ethynyl) pyridin- Pyridin-2-yl) -3- (1H-tetrazol-1-yl) benzyloxy) propan-2-ol) (44);

Phenyl) ethynyl) pyridin-2-yl) -2- (4-fluorophenyl) (1- (5 - ((4- (4 - ((((4-fluorophenyl) -1,1-difluoro- 2- (2,4-difluorophenyl) -1,1-difluoro-3- (1H) -quinolinone -tetrazol-1-yl) propan-2-ol) (45);

Methyl) amino) methyl < RTI ID = 0.0 > (2, < / RTI > 2-yl) -3- (1H-tetrazol-1-yl) propan- Pyridin-2-yl) -3- (1H-tetrazol-3-ylmethyl) benzyloxy) 1-yl) propan-2-ol) (46);

(5 - ((4- (4 - ((2-hydroxypropyl) (methyl) amino) methyl) benzyloxy) -1,1-difluoro- Phenyl) ethynyl) pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan- Pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2- ol) (47);

2 - ((4 - ((4 - ((6- (2- (2,4-difluorophenyl) -1,1-difluoro-2- Methyl) benzylamino) methyl) -1 H-imidazole-1-carbaldehyde (2 - ((4 - ((4- - (2,4-difluorophenyl) -1,1-difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3- yl) ethynyl) phenoxy) lt; / RTI > imidazole-1-carbaldehyde) (48);

2 - (((4 - ((4 - ((6- (2- (2,4-difluorophenyl) -1,1-difluoro-2- Methyl) benzyl) (methyl) amino) methyl) -1H-imidazole-1-carbaldehyde (2- ((6- (2- (2,4-difluorophenyl) -1,1-difluoro-2-hydroxy-3- (1H- tetrazol- 1- yl) propyl) pyridin- benzyl) (methyl) amino) methyl) -1H-imidazole-1-carbaldehyde) (49);

Hydroxy-3- (1H-tetrazol-1-yl) -1H-pyrazole-3- Yl) ethynyl) phenoxy) methyl) benzyl) -1 H-imidazole-4-carbonitrile (1- (4- ( 3-yl) ethynyl) phenoxy) methyl) benzyl) -1H-imidazole-4-carbonitrile) ( 50);

Hydroxy-3- (1H-tetrazol-1-yl) -1H-pyrazole-3- (4- ((4- ((6- (2-fluoro-phenyl) -2-methyl- (2,4-difluorophenyl) -1,1-difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3- yl) ethynyl) phenoxy) 1H-imidazole-2-carboxamide) (51);

Phenyl) -1,1-difluoro-1- (5 - ((4- (4-methylpiperazin-1-yl) methyl) benzyloxy) phenyl) Ethynyl) pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan- (4 - ((4-methylpiperazin-1-yl) methyl) benzyloxy) phenyl) ethynyl) pyridin-2-yl) -3- (1H- tetrazol- );

Hydroxy-3- (1H-tetrazol-1-yl) -1H-pyrazole-3- Benzyl) piperazine-1-carbaldehyde (4- (4 - ((4 - ((6- (2- (2,4- difluorophenyl) -1,1-difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3-yl) ethynyl) phenoxy) methyl) benzyl) piperazine-1-carbaldehyde) (53);

Ethynyl) pyridin-2-yl (4-fluorophenyl) -1,1-difluoro-1- (2,4- difluorophenyl) -1,1-difluoro-1- (5 - ((4- (4- (morpholinomethyl) ) benzyloxy) phenyl) ethynyl) pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol) (54);

Hydroxy-3- (1H-tetrazol-1-yl) -1H-pyrazole-3- 2- (2,4-difluorophenyl) propyl) pyridin-3-yl) ethynyl) phenoxy) methyl) benzyl) imidazolidin- -1,1-difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3-yl) ethynyl) phenoxy) methyl) benzyl) imidazolidin-2-one) (55);

Hydroxy-3- (1H-tetrazol-1-yl) -1H-pyrazole-3- Methyl) benzyl) imidazolidin-2,4-dione (1- (4 - ((4 - ((6- (2- 2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3-yl) );

Ethynyl) pyridin-2-yl) -2- (2,4-di (tert-butyldimethylsilyloxy) Fluoro- phenyl) -1,1-difluoro-3- (1H-tetrazol-1-yl) propan- 2-yl) -2- (2,4-difluorophenyl) -1,1-difluoro-3- (1H-tetrazol- 1 -yl) propan-2-ol ) 57;

(4- (2- (4 - ((6- (2- (2,4-difluorophenyl) -1,1-difluoro-2- ) Pyridin-3-yl) ethynyl) phenyl) -2-hydroxyethyl) benzonitrile (4- (2- (4- difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3-yl) ethynyl) phenyl) -2-hydroxyethyl) benzonitrile 58;

Hydroxy-3- (1H-tetrazol-1-yl) -1H-pyrazole-3- (4H) -2-methylpentan-3-yl) -1H-1,2,4-triazole-5 (4H) ) -One (4- (4 - ((4 - ((6- (2- (2,4-difluorophenyl) -1,1- difluoro-2- hydroxy- 3- (1H- tetrazol- ) pyridin-3-yl) ethynyl) phenoxy) methyl) phenyl) -1 - ((S) -2-methylpentan-3-yl) -1H-1,2,4-triazol-5 (4H) 59);

(2-hydroxy-1- (1H-pyrazol-1-yl) ethyl) -1,1-difluoro-1- (5- 2-yl) -3- (1H-tetrazol-1-yl) propan- Pyridin-2-yl) -3- (1H-tetrazol-1-yl) ethyl) benzyloxy) 1-yl) propan-2-ol) (60);

2- (2,4-difluorophenyl) -1- (5 - ((4- (4- (1- (dimethylamino) -2-hydroxyethyl) phenyl) ethynyl) pyridin- (2,4-difluorophenyl) -1- (5 - ((4- (4-fluorophenyl) (1H) -difluoro-3- (1H-tetrazol-1-yl) propan-2-ol) (61) ;

Ethynyl) pyridin-2-yl) -1- (5 - ((4- (3- (hydroxymethyl) benzyloxy) phenyl) 2- (2,4-difluorophenyl) -1,1-difluoro-1- (5 - ((4- (3- (hydroxymethyl) benzyloxy) phenyl) ethynyl) pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol) (62);

2- (2,4-difluorophenyl) -1- (5 - ((4- (3 - ((dimethylamino) methyl) benzyloxy) phenyl) ethynyl) pyridin- 2- (2,4-difluorophenyl) -1- (5 - ((4- (3 - ((dimethylamino) methyl) benzyloxy phenyl) ethynyl) pyridin-2-yl) -1,1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol) (63);

Ethynyl) pyridin-2-yl) -2- (2,4-difluoro-phenyl) (1 - (5 - ((4- (3 - ((1H-pyrazol-1-yl) methyl) -1,1-difluoro-3- 2- (2,4-difluorophenyl) -1,1-difluoro-3- (1H-tetrazol-1-yl) propan- ;

2- (2,4-difluorophenyl) -1- (5 - ((4- (3- (1- (dimethylamino) -2-hydroxyethyl) phenyl) ethynyl) (2,4-difluorophenyl) -1- (5 - ((4- (3-fluorophenyl) -1- (1-methyl-2-hydroxyethyl) benzyloxy) phenyl ethynyl) pyridin-2-yl) -1,1-difluoro-3- (1H- tetrazol- ;

(2-hydroxy-1- (1H-pyrazol-1-yl) ethyl) -1,1-difluoro-1- (5- 2-yl) -3- (1H-tetrazol-1-yl) propan- Pyridin-2-yl) -3- (1H-tetrazol-1-yl) ethyl) benzyloxy) 1-yl) propan-2-ol) (66);

Phenyl) ethynyl) pyridin-2-yl) - (3-chloro-lH- Synthesis of 2- (2,4-difluorophenyl) -1,1-difluoro-3- (1H-tetrazol-1-yl) propan- (3-chloro-1H-1,2,4-triazol-1-yl) methyl) benzyloxy) phenyl ethynyl) pyridin-2-yl) -2- (2,4- difluorophenyl) -1,1- 3- (1H-tetrazol-1-yl) propan-2-ol) (67);

2- (2,4-difluorophenyl) -1- (5 - ((4- ((5 - ((dimethylamino) methyl) thiophen-2- yl) methoxy) phenyl) ethynyl) 2- (2,4-difluorophenyl) -1- (5 - ((4 - (((1 H) -trifluorophenyl) -1- 2-yl) -1,1-difluoro-3- (1H-tetrazol-1-yl) propan- (68);

Yl) methoxy) phenyl) ethynyl) pyridin-2-yl) -2- (4-fluorophenyl) (1- (5 - ((4 - ((5 - (((4-fluorophenyl) -1,1-difluoro- Pyridin-2-yl) -2- (2,4-difluorophenyl) -1,1-difluoro-3- (lH- pyrazol- tetrazol-1-yl) propan-2-ol) (69);

Methyl-1,1-difluoro-2-hydroxy-3-methylbutyl) pyridin-3-yl) Yl) methyl) -1,1-difluoro-2-hydroxy-3- (2-hydroxyethyl) phenoxy) methyl) benzonitrile methylbutyl) pyridin-3-yl) ethynyl) phenoxy) methyl) benzonitrile) (70);

Methyl-1,1-difluoro-2-hydroxy-3,3-dimethylbutyl) pyridine-3- 1-yl) methyl) -1,1-difluoro-2-hydroxy-ethyl) phenoxy) methyl) benzonitrile (prepared from 4 - {(4- { 3,3-dimethylbutyl) pyridin-3-yl) ethynyl) phenoxy) methyl) benzonitrile) (71);

4 - ((4 - ((6- (2-cyclopropyl-1,1-difluoro-2-hydroxy- (2-cyclopropyl-1,1-difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin- 3-yl) ethynyl) phenoxy) methyl) benzonitrile) (72);

Ethynyl) pyridin-2-yl) -2- (2, 4-difluorophenyl) ethoxy] (1- (5 - ((4 - ((5- (difluoromethyl) thiophen-2-yl) methoxy phenyl) ethynyl) pyridin-2-yl) -2- (2,4-difluorophenyl) -1,1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol) (73);

Ethynyl) pyridin-2-yl) -2- (2, 4-difluorophenyl) -1, (5 - ((4 - ((5-chlorothiophen-2-yl) methoxy) phenyl) ethynyl) pyridin- 2-yl) -2- (2,4-difluorophenyl) -1,1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol) (74);

2- (2,4-difluorophenyl) -1- (5 - ((4- (4 - ((dimethylamino) methyl) -3-fluorobenzyloxy) phenyl) ethynyl) pyridin- 2- (2,4-difluorophenyl) -1- (5 - ((4- (4 - ((dimethylamino) ) methyl) -3-fluorobenzyloxy) phenyl) ethynyl) pyridin-2-yl) -1,1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol) (75);

Ethynyl) pyridin-2-yl) -2- (2,4-difluorophenyl) -1- (5 - ((4- (4- fluorophenyl) (1- (5 - ((4- (4- (difluoromethyl) -3-fluorobenzyloxy) phenyl) ethynyl) pyridin- 2-yl) -2- (2,4-difluorophenyl) -1,1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol) (76);

Ethynyl) pyridin-2-yl) -2- (2, 4-dihydro- (1- (5 - ((4- (4 - ((1H-pyrazol-1-yl) pyridin-2-yl) -2- (2,4-difluorophenyl) -1,1-difluoro-3- (1H-tetrazol-1-yl) propan- 2-ol) (77);

Ethynyl) pyridin-2-yl) -2- (4-fluoro-4- (4- (4- (1- (5 - ((4- (4 - ((4-fluorophenyl) -1,1-difluoro-3- pyridin-2-yl) -2- (2,4-difluorophenyl) -1,1-difluoro-3- (1H- tetrazol-1-yl) propan-2-ol) (78);

2- (2,4-difluorophenyl) -1,1-difluoro-1- (5 - ((4- (4-chlorophenyl) 2- (2,4-difluorophenyl) -1,1-difluoro-1- (5 - ((4 - ((4- chlorophenyl) (hydroxy) methyl) phenyl) ethynyl) pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol) (79);

1- (5 - ((4- (2- (4-chlorophenyl) -1-hydroxyethyl) phenyl) ethynyl) pyridine 2- (2,4-difluorophenyl) -1,1-difluoro-1- (5 - ((4- ( 2- (4-chlorophenyl) -1-hydroxyethyl) phenyl) ethynyl) pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol) (80);

(5 - ((4- (1-hydroxy-2- (2,2,2-trifluoroethoxy) ethyl) -1,1- Phenyl) ethynyl) pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan- Pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol ) 81;

Hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridine-1-carboxylic acid 3-yl) ethynyl) phenyl) -3,3,4,4,4-pentafluorobutan- l-ol (1- (4- (6- (2- 1-difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3- yl) ethynyl) phenyl) -3,3,4,4,4- pentafluorobutan- );

Ethynyl) pyridin-2-yl) -2- (2, 4-difluorophenyl) (1- (5 - ((4- (1-amino-2,2,3,3,3) -propan- yl) propan-2-ol) (83) The title compound was prepared in a manner similar to that described in Example 1, ;

(1 - (4 - ((6- (2- (2,4-difluorophenyl) -1,1-difluoro-2- Trifluoromethanesulfonamide (N- (1- (4 - ((6- (2- (2,4-difluorophenyl) - 1,1-difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3-yl) ethynyl) phenyl) propyl) -1,1,1-trifluoromethanesulfonamide) (84);

Hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridine-1-carboxylic acid (4 - ((6- (2- (2,4-difluorophenyl) - 1, 2- dihydroxypropyl) (1-difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) 85);

2-yl) -2- (2,4-difluorophenyl) -1,1-difluoro-3 (trifluoromethyl) Pyridin-2-yl) -2- (2-pyridyl) -1H-pyrazolo [3,4-d] pyrimidin- -difluorophenyl) -1,1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol) (86).

In another aspect, the invention provides a pharmaceutical composition comprising a compound of any one of formulas (e.g., Formula I-XVII) of the invention and a pharmaceutically acceptable carrier.

In another aspect, the invention includes contacting an object with any one of the formulas of the invention (e. G., Formula I-XVII) in an amount and condition sufficient to modulate the activity of the metal enzyme (Metalloenzyme) activity of a subject to be treated.

In another aspect, the invention provides a method of treating a disorder in a subject, comprising administering to a subject in need thereof an effective amount of any one of the compounds of the present invention (e. G., Formula I-XVII) , A method of treating a subject having or susceptible to a disorder or disease, wherein the subject is identified as requiring treatment of a disorder or disease.

In another aspect, the subject is a non-human animal.

The methods of the invention include those wherein the disorder or disease is associated with one or more of the following pathogenic fungi: Absidia corymbifera, Ajellomyces dermatitidis, For example, Arthroderma benhamiae, Arthroderma fulvum, Arthroderma gypseum, Arthroderma incurvaturn, Arthroderma otae, Aspergillus flavus, Aspergillus fumigates, Aspergillus niger, Blastomyces dermatitidis, Aspergillus spp., Aspergillus niger, Aspergillus niger, Blastomyces dermatitidis, Candida albicans, Candida glabrata, Candida guilliermondii, Candida albicans, Candida albicans, Candida species such as Candida krusei, Candida parapsilosis, Candida tropicalis, Candida pelliculosa, Cladophialophora carrionii, Such as Coccidioides immitis, Coccidioides posadasii, Cryptococcus neoformans, Cunninghamella sp., Epidermophyton floccosum, Exophiala dermatitidis, Filobasidiella neoformans, Fonsecaea pedrosoi, Fusarium solani, Geotrichum candidum, and the like. Histoplasma capsulaturn, Hortaea werneckii, Issatschenkia orientalis, Madurella gris, ae, Malassezia fur fur, Malassezia globosa, Malassezia obtuse, Malassezia pachydermatis, Malassezia furfur, Malassezia restricta, Malassezia slooffiae, Malassezia sympodialis, Microsporum canis, Microsporum fulvum, Microsporum fulvum, Microsporum gypseum, Mucor circinelloides, Nectria haematococca, Paecilomyces variotii, Paracoccidioides brasiliensis, Paracoccidioides brasiliensis, , Penicillium marneffei, Pichia anomala, Pichia guilliermondii, Pneumocystis carinii, Succulent cherry, Pseudallescheria boydii, Rhizopus oryzae, Rhodotorula rubra, Scedosporium apiospernium, Schizophyllum commune, sporotrichic acid, A medicinal herb such as Sporothrix schenckii, Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton verrucosum, Trichophyton violaceum, Trichosporon asahi asahii, Trichosporon cutaneum, Trichosporon inkin, and Trichosporon mucoides.

The method of the present invention is characterized in that the disorder or disease is selected from the group consisting of Aspergillosis, Blastomycosis, Candidiasis, Chromomycosis, Coccidioidomycosis, Cryptococcosis (Eg, Cryptococcosis), dermatophytoses, histoplasmosis, keratomycosis, lobomycosis, malassezia infection, mucormycosis, paracoscisosis, Or a disease or disorder of Paracoccidioidomycosis, Penicillium marneffei infection, Phaeohyphomycosis, Pneumocyctis pneumonia, or Rhinosporidiosis. .

The method can be used for the treatment of Chagas disease (Genus Trypanosoma), African trypanosomiasis (Genus Trypanosoma), leishmaniasis (Genus Leishmania) , Tuberculosis (Genus Mycobacterium), leprosy (Genus Mycobacterium), malaria (Genus Plasmodium), or tinea (tobacco) capitis, ringworm, corporis ringworm, pedis, tonsurans, versicolor.

In one aspect, the invention provides a method of treating a subject having a metal enzyme-related disorder or disease, comprising administering to the subject an effective amount of any one of the formulas (e.g., Formula I-XVII) Thereby providing a method of treating a susceptible subject.

In another aspect, the invention provides a method of treating a disorder in a subject, comprising administering to a subject in need thereof an effective amount of any one of the compounds of the present invention (e. G., Formula I-XVII) , A method of treating a subject having or susceptible to a metal enzyme related disorder or disease, wherein said subject is identified as requiring treatment of a disorder or disease associated with a metal enzyme.

In another aspect, the invention provides a method of treating a subject in need thereof by administering to a subject in need thereof an effective amount of any one of the compounds of formula (I-XVII) or a pharmaceutical composition thereof, Wherein the subject is suffering from a disorder or disease associated with a metal enzyme, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, Are identified as needed.

The method of the present invention is based on the use of 4-hydroxyphenyl pyruvate dioxygenase, 5-lipoxygenase, adenosine deaminase, alcohol dehydrogenase, dehydrogenase, aminopeptidase N, angiotensin converting enzyme, aromatase (CYP19), calcineurin, carbamoyl phosphate synthetase, But are not limited to, a carbonic anhydrase family, a catechol o-methyl transferase, a cyclooxygenase family, dihydropyrimidine dehydrogenase-1, , DNA polymerase, farnesyl diphosphate synthase, farnesyl transferase, fumaric acid lidocite (GABA aminotransferase), HIF-prolyl hydroxylase, histone deacetylase family, HIV integrase, and the like), fumarate reductase, GABA aminotransferase, HIV-1 reverse transcriptase, isoleucine tRNA ligase, lanosterol demethylase (CYP51), matrix metalloprotease family (HIV-1 reverse transcriptase) , Thionine aminopeptidase, neutral endopeptidase, nitric oxide synthase family, phosphodiesterase III, phosphodiesterase IV, phosphodiesterase V, phosphodiesterase V, (phosphodiesterase V), pyruvate ferredoxin oxidoreductase, renal peptidase, ribose A ribonucleoside diphosphate reductase, a thromboxane synthase (CYP5a), a thyroid peroxidase, a tyrosinase, a urease, Or xanthine oxidase. ≪ Desc / Clms Page number 7 >

The method of the present invention is based on the use of 1-deoxy-d-xylulose-5-phosphate reductoisomerase (DXR), 17-alpha hydroxyacylase -alpha hydroxylase (CYP17), aldosterone synthase (CYP11B2), aminopeptidase P, anthrax lethal factor, arginase, beta-lactamase beta -lactamase, cytochrome P450 2A6, d-ala d-ala ligase, dopamine beta-hydroxylase, endothelin conversion, Endothelin converting enzyme-1, glutamate carboxypeptidase II, glutaminyl cyclase, glyoxalase, heme oxygenase, HPV / HSV E1 helicase, HPV / HSV E1 helicase, indoleamine 2,3-dioxygenase, Leucotriene A4 hydrolase, methionine aminopeptidase 2, peptide deformylase, phosphodiesterase VII, relaxase, retinoic acid hydrate, (CYP26), TNF-alpha converting enzyme (TACE), UDP- (3-O- (R-3-hydroxymyristoyl) (UDP- (3-O- (R-3-hydroxymyristoyl)) - N-acetylglucosamine deacetylase (LpxC), vascular adhesion protein- Or vitamin D hydroxylase (CYP24). ≪ / RTI >

The methods herein include those wherein said disease or disorder is a cancer, cardiovascular disease, inflammatory disease, infectious disease, metabolic disease, ophthalmic disease, central nervous system (CNS) disease, urinary disease, or digestive system disease.

The method of the present invention is further characterized in that the disease or disorder is selected from the group consisting of prostate cancer, breast cancer, inflammatory bowel disease, psoriasis, systemic fungal infection, skin structure fungal infection, mucosal fungal infection, onychomycosis.

The methods described herein include methods in which the subject is identified by the need for the treatment specifically mentioned. It may be the judgment of the subject or health care professional to identify the subject in need of such treatment and may be subjectively (e. G., Opinion) or objective (e. G., Measurable by an experimental or diagnostic method) It can be one.

Another aspect of the invention is a composition comprising a compound of the formula (e. G., Formula I-XVII) and an agriculturally acceptable carrier.

Another aspect of the invention is a method of treating or preventing a metal enzyme associated with a disease or disorder on the interior or surface of a plant, comprising contacting the plant with a compound of the present invention.

Another aspect of the invention is a method of inhibiting metalloenzyme activity of the interior or surface of a plant comprising contacting the compound of the present invention.

Justice

For a better understanding of the invention, certain terms are hereby defined for convenience.

As used herein, "treating" a term disorder refers to a condition that "prevents," " alleviates, "" alleviates" and / . The terms " treating "and" treating "refer to a method of alleviating or attenuating a disease and / or its accompanying symptoms. In the present invention, "treating" is used to refer to any of the following: "preventing," " blocking, "" suppressing," " attenuating, " Inversion "and" reducing occurrence ".

As used herein, the term "inhibiting" includes "preventing "," decreasing " Is distinguished from "enzyme inhibition" (e. G., Metal enzyme inhibition) and is described below.

The term "modulating" means increasing or decreasing the activity of an enzyme in response to exposure to a compound of the invention.

The term " separated, "" refined," or "biologically pure" refers to a material that is substantially or essentially removed from components found in its original state. Purity and identity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography. In particular, in an embodiment, the compound is at least 85% pure, preferably at least 90% pure, more preferably at least 95% pure, and most preferably at least 99% pure.

The term " administering "or" administering "encompasses the route by which a compound is introduced into a subject to perform its intended function. Examples of routes of administration that may be used are injection (subcutaneous, intravenous, parenteral, peritoneal, intraspinal), local, oral, inhalation, rectal and transdermal.

The term "effective amount" encompasses an amount effective at dosages and times necessary to achieve the desired result. The effective amount of the compound may vary depending on factors such as the disease stage of the subject, age, body weight, and the ability of the compound to elicit a desired response to the subject. The dosage regimen may be adjusted to provide an optimal therapeutic response. An effective amount is also the amount of the inhibiting compound that exceeds the toxic or deleterious effect by a therapeutically beneficial effect.

As used herein, the terms "systemic administration," "systemic administration," "peripheral administration," and "peripheral administration" refer to the administration of a metabolic or other similar process (S), agent (s), or other substance (s) participating in the treatment.

The term "therapeutically effective amount" means an amount of a compound that is sufficiently administered to prevent or alleviate the occurrence of one or more symptoms of the disease or disorder being treated.

The therapeutically effective amount (i.e., effective dose) of the compound may range from about 0.005 μg / kg to about 200 mg / kg of body weight, preferably from about 0.01 mg / kg to about 200 mg / kg, More preferably from about 0.015 mg / kg to about 30 mg / kg. In another embodiment, the therapeutically effective amount ranges from about 1.0 pM to about < RTI ID = 0.0 > 10 [mu] M. It will be appreciated by those of ordinary skill in the art that certain factors, including but not limited to the severity of the disease or disorder, previous treatment, the health and / or age of the subject, and the age of the subject, past history, may affect the dosage required to effectively treat the subject I can understand. Moreover, treating a subject with a therapeutically effective amount of a compound may comprise a single treatment, or preferably a continuous treatment. In one embodiment, the subject is a compound in the range of about 0.005 μg / kg to about 200 mg / kg of body weight, once per day for about 1 to 10 weeks, preferably for 2 to 8 weeks, About 3 to 7 weeks, and even more preferably about 4, 5, or 6 weeks. In another embodiment, the subject can be treated daily for many years under chronic disease or illness. It is also understood that the effective amount of the compound used for treatment may be increased or decreased depending on the particular treatment method.

The term "chiral" refers to a molecule having non-overlapping properties of a mirror partner, while the term "aciral " means a superimposable molecule of a mirror partner of a molecule.

The term "diastereoisomer" means a stereoisomer having two or more asymmetric centers and the molecules of one another not being mirror images of each other.

The term "enantiomer" refers to two stereoisomers of compounds that do not overlap each other in enantiomerism. An equimolar mixture of two enantiomers is called a "racemic mixture" or "racemate".

The term "isomer" or "stereoisomer" refers to a compound having the same structure but differing in the arrangement of atoms or groups in space.

The term "prodrug" includes compounds having moieties that can be metabolized in vivo. Generally, the prodrug can be metabolized to an active drug by an esterase or other mechanism. Examples of prodrugs and their uses are well known in the art to which the invention pertains (see, for example, Berge et al. (1977) "Pharmaceutical Salts ", J. Pharm . Sci . 66: 1-19). Prodrugs can be prepared in situ during the final isolation and purification of the compound or the free acid form of the purified compound or the hydroxyl can be prepared by reacting separately with a suitable esterifying agent . The hydroxyl group can be converted to an ester through treatment of the carboxylic acid. Examples of prodrug moieties include substituted and unsubstituted, branched or unbranched alkyl ester moieties (e. G., Propionic acid esters), lower alkenyl esters, di-lower alkyl Acyloxy lower alkyl esters (e.g., acetyloxymethyl esters), acyloxy lower alkyl esters (e.g., pivaloyloxymethyl esters), amino-lower alkyl esters Aryl ester (phenyl ester), aryl-lower alkyl ester (e.g. benzyl ester), substituted (e.g. by methyl, halo, or methoxy substituents), aryl and aryl-lower alkyl ester, -Alkylamides, di-lower alkylamides, and hydroxyamides. Preferred prodrug moieties are propionic esters and acyl esters. Also included are prodrugs that are converted to the active form through other mechanisms in vivo. In one aspect, the compounds of the present invention are any prodrugs of the formulas herein.

The term "subject" means an animal such as, but not limited to, a mammal, including, but not limited to, a primate (e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, rat,

The term "one ", as used in the present invention including claims, means" one or more ". Thus, for example, a "sample" includes a plurality of samples if the context clearly does not define the opposite (e.g., a plurality of samples).

Throughout the specification and claims, the terms "including," "including," and "including" are used in a non-exclusive sense unless the context otherwise requires.

As used herein, the term "about" when referring to a numerical value refers to a range of values from a particular amount in the range of +/- 20%, in some embodiments +/- 10%, in some embodiments +/- 5%, in some embodiments +/- 1% . In some embodiments, the variation includes a variation of +/- 0.1%, and the variation is an extent suitable to perform the disclosed method or to be applied to the disclosed composition.

As used herein, the term "inhibitor" means a molecule that exhibits activity inhibiting a metal enzyme. Here, "inhibit" is to decrease the activity of the metal enzyme compared to the activity of the metal enzyme when no inhibitor is present. In some embodiments, the term "inhibit" refers to the activity of a metal enzyme by at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 50% %, At least about 80%, at least about 90%, or at least about 95%. In another embodiment, "inhibiting" means reducing the activity of a metal enzyme from about 5% to about 25%, from about 25% to about 50%, from about 50% to about 75%, or from about 75% to 100% it means. In some embodiments, "inhibiting" means reducing the activity of the metal enzyme by about 95% to 100%, e.g., 95%, 96%, 97%, 98%, 99%, or 100% . The reduction may be measured using various techniques well known in the art to which the present invention belongs. Specific assays for measuring individual activities are described below.

Further, the compounds of the present invention include olefins having respective geometries: "Z" means being referred to as a " Quot; form "). For chiral center nomenclature, the terms "d" and "l" are defined by the IUPAC rules. The use of diastereoisomers, racemates, epimers and enantiomeric terms will be used within the general context to describe the stereochemistry of the preparation.

As used herein, the term "alkyl" means a straight-chain or branched hydrocarbon group containing from 1 to 12 carbon atoms. The term "lower alkyl" means a C1-C6 alkyl chain. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, tert-butyl, and n-pentyl. The alkyl group may be optionally substituted with one or more substituents.

The term "haloalkyl" refers to an alkyl group substituted by one or more halo substituents. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, bromomethyl, chloromethyl and 2,2,2-trifluoroethyl.

The term "alkenyl" means an unsaturated hydrocarbon chain, which may be a straight chain or branched chain comprising from 2 to 12 carbon atoms and at least one carbon-carbon double bond. The alkenyl group may be optionally substituted with one or more substituents.

The term "arylalkenyl" means a straight or branched chain containing from 2 to 12 carbon atoms and at least one carbon-carbon double bond attached to an aryl moiety of one or more sp ² hybridized carbons of an alkenyl unit ≪ / RTI > The alkenyl group may be optionally substituted with one or more substituents.

The term "alkynyl" means an unsaturated hydrocarbon chain which may be a straight chain or branched chain comprising from 2 to 12 carbon atoms and at least one carbon-carbon triple bond. The alkynyl group may be optionally substituted with one or more substituents.

The term "arylalkynyl" means a saturated or unsaturated, saturated or unsaturated, saturated or unsaturated, saturated or unsaturated, saturated or unsaturated, saturated or unsaturated, saturated or unsaturated ≪ / RTI > The alkynyl group may be optionally substituted with one or more substituents.

The sp ² or sp carbon of the alkenyl group and the alkynyl group may be, respectively, an attachment point of an alkenyl or alkynyl group, respectively.

The term "alkoxy" means an -O-alkyl substituent.

The term "halogen", "halo" or "halo" as used herein means -F, -Cl, -Br or -I.

The term "alkylthio" means an -S-alkyl substituent.

The term "alkoxyalkyl" means an -alkyl-O-alkyl substituent.

The term "haloalkoxy" means -O-alkyl substituted by one or more halo substituents. Examples of haloalkoxy groups include trifluoromethoxy, and 2,2,2-trifluoroethoxy.

The term "haloalkoxyalkyl" means -alkyl-O-alkyl and the alkyl is substituted with one or more halo substituents.

The term "haloalkylaminocarbonyl" means -C (O) -amino-alkyl and the alkyl is substituted with one or more halo substituents.

The term "haloalkylthio" means -S-alkyl substituted by one or more halo substituents. Examples of haloalkylthio include trifluoromethylthio, and 2,2,2-trifluoroethylthio.

The term "haloalkylcarbonyl" means -C (O) -alkyl substituted by one or more halo substituents. An example of a haloalkylcarbonyl group includes trifluoroacetyl.

The term "cycloalkyl" means a hydrocarbon 3-8 atomic monocyclic or 7-14 atomic bicyclic ring system comprising at least one saturated ring or at least one nonaromatic ring, wherein the non- May have a slight degree of unsaturation. The cycloalkyl group may be optionally substituted with one or more substituents. In one embodiment, the 0, 1, 2, 3, or 4 atoms of each ring of the cycloalkyl group may be substituted by substituents. Representative examples of cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cyclobutyl, cycloheptyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl and cyclohexadienyl, and the like.

The term "cycloalkoxy" means an-O-cycloalkyl substituent.

The term "cycloalkoxyalkyl" means an -alkyl-O-cycloalkyl substituent.

The term "cycloalkylalkoxy" means an -O-alkyl-cycloalkyl substituent.

The term "cycloalkylaminocarbonyl" means a -C (O) -NH-cycloalkyl substituent.

The term "aryl" refers to a hydrocarbon monocyclic, bicyclic or tricyclic aromatic ring system. The aryl group may be optionally substituted with one or more substituents. In one embodiment, the 0, 1, 2, 3, 4, 5 or 6 atoms of each ring of the aryl group may be substituted by substituents. Examples of aryl groups include phenyl, naphthyl, anthracenyl, fluorenyl, indenyl and azulenyl, and the like.

The term "aryloxy" means an-O-aryl substituent.

The term "arylalkoxy" means an-O-alkyl-aryl substituent.

The term "arylalkylthio" means an-S-alkyl-aryl substituent.

The term "arylthioalkyl" means an -alkyl-S-aryl substituent.

The term "arylalkylaminocarbonyl" means a -C (O) -amino-alkyl-aryl substituent.

The term "arylalkylsulfonyl" means a -S (O) ₂ -alkyl-aryl substituent.

The term "arylalkylsulfinyl" means a -S (O) -alkyl-aryl substituent.

The term "aryloxyalkyl" means an -alkyl-O-aryl substituent.

The term "alkylaryl" means an-aryl-alkyl substituent.

The term "arylalkyl" means an -alkyl-aryl substituent.

The term "heteroaryl" refers to an aromatic 5-8 atomic mono comprising 1-4 ring heteroatoms when monocyclic, 1-6 heteroatoms when bicyclic, or 1-9 heteroatoms when tricyclic Cyclic, 8-12 atomic bicyclic, or 11-14 atomic tricyclic ring system, wherein the heteroatom is selected from O, N or S, and the remaining ring atoms are carbon (unless otherwise indicated With appropriate hydrogen atoms if not). The heteroaryl group may be optionally substituted with one or more substituents. In one embodiment, zero, one, two, three, or four atoms of each ring of the heteroaryl group may be substituted by substituents. Examples of heteroaryl groups include, but are not limited to, pyridyl, furanyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl, The compounds of formula (I) are preferably selected from the group consisting of thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, isoquinolinyl, indazolyl, and the like.

The term "heteroaryloxy" means an -O-heteroaryl substituent.

The term "heteroarylalkoxy" means an -O-alkyl-heteroaryl substituent.

The term "heteroaryloxyalkyl" means an -alkyl-O-heteroaryl substituent.

The term "nitrogen-containing heteroaryl" includes 1-4 ring nitrogen heteroatoms for monocyclic, 1-6 ring nitrogen heteroatoms for bicyclic, or 1-9 ring nitrogen heteroatoms for tricyclic ≪ / RTI >

The term "heterocycloalkyl" refers to nonaromatic 3-8 atoms containing 1-3 heteroatoms in the case of monocyclic, 1-6 heteroatoms in the case of bicyclic, or 1-9 heteroatoms in the case of tricyclic Monocyclic, 7-12 atomic bicyclic, or 10-14 atomic tricyclic ring system, wherein said heteroatom is selected from O, N, S, B, P or Si, The ring system is completely saturated. The heterocycloalkyl group may be optionally substituted with one or more substituents. In one embodiment, the 0, 1, 2, 3, or 4 atoms of each ring of the heterocycloalkyl group may be substituted by substituents. Representative heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,3-dioxolane 1,3-dioxolane, tetrahydrofuranyl, tetrahydrothienyl and thienyl, and the like.

The term "alkylamino" means an amino substituted group further substituted with one or more alkyl groups. The term "aminoalkyl" means an alkyl substituent further substituted with one or more amino groups. The term "hydroxyalkyl" or "hydroxylalkyl" means an alkyl group further substituted with one or more hydroxyl groups. The alkyl or aryl moieties of alkylamino, aminoalkyl, mercaptoalkyl, hydroxyalkyl, mercaptoalkoxy, sulfonylalkyl, sulfonylaryl, alkylcarbonyl, and alkylcarbonylalkyl may optionally be substituted with one or more substituents have.

Acids and bases useful in the methods herein are as known in the art. The acid catalyst can be any inorganic (e.g., hydrochloric, sulfuric, nitric, trichloride) or organic (e.g., camphorsulfonic acid, p-toluenesulfonic acid, acetic acid, ytterbium ytterbium) . Acids are used catalytically or stoichiometrically to promote chemical reactions. The base can be any inorganic in nature (e.g., sodium bicarbonate, potassium hydroxide) or an organic (e.g., triethylamine, pyridine) base chemical. The base is used catalytically or stoichiometrically to promote the chemical reaction.

An alkylating agent is any agent that can affect the alkylation of the functional group in question (e.g., an oxygen atom in an alcohol, a nitrogen atom in an amino group). Alkylating agents are known in the art, including references cited herein, and include alkyl halides (e.g., methyl iodide, benzyl bromide or chloride), alkyl sulfates (e.g., Methyl sulfate), or other alkyl-leaving group combinations known in the art. Leaving groups are any stable chemical species that can fall off the molecule during the course of the reaction (e. G., Elimination, displacement), which is known in the art to which the present invention pertains, including references cited therein, (E.g. O-, Cl-, Br-, F-), hydroxy, alkoxy (e.g. -OMe, -Ot-Bu), acyloxy anion ) CF ₃ ), sulfonates (e.g., mesyl, tosyl), acetamides (e.g., -NHC (O) Me), carbamates ), Phosphonates (e.g., -OP (O) (OEt) ₂ ), water or alcohols (conditions for protonation), and the like.

In certain embodiments, substituents of any group (such as, for example, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, heterocycloalkyl) May be at any atom of the group where the substituent may be substituted (for example, with an alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, heterocycloalkyl, Any such group may be optionally substituted with one or more (which may be the same or different) substituents by replacing each hydrogen atom. Examples of suitable substituents are alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halogen, haloalkyl, cyano, nitro, alkoxy, aryloxy, hydroxyl Alkylcarbonyl, alkoxycarbonyl, alkylcarbonyloxy, aryloxycarbonyl, heteroaryloxy, heteroaryloxycarbonyl, heteroaryloxycarbonyl, heteroaryloxycarbonyl, heteroaryloxycarbonyl, Thio, mercapto, mercaptoalkyl, arylsulfonyl, amino, aminoalkyl, dialkylamino, alkylcarbonylamino, alkylaminocarbonyl, alkoxycarbonylamino, alkylamino, arylamino, diarylamino, alkylcarbonyl , Or arylamino-substituted aryl; Arylalkylamino, aralkylaminocarbonyl, amido, alkylaminosulfonyl, arylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, imino, carbamoido, carbamyl, thio Thioureido, thiocyanato, sulfamoido, sulfonylalkyl, sulfonylaryl, mercaptoalkoxy, N-hydroxyamidinyl, or N'-aryl, N " -hydroxy But are not necessarily limited thereto.

The compounds of the present invention can be prepared by means known in the art of organic synthesis. Methods for optimizing the reaction conditions necessary to minimize competitive byproducts are known in the art. Reaction optimization and scale-up are preferably high speed parallel synthesis apparatus (high-speed parallel synthesis equipment) and computer-may be used to control micro-reactor (computer-controlled microreactor) (for example, Design And Optimization in Organic Synthesis, 2 ^nd Edition, Carlson R, Ed, 2005; Elsevier Science Ltd .; Jahnisch, K et al., Angew. Chem. Int. Ed. Eng. 2004 43: 406; Additional reaction procedures and protocols may be performed using conventional search-and-retrieval database software, such as SciFinder® (CAS division of the American Chemical Society) and CrossFire Beilstein® (Elsevier MDL) Search, or by a person skilled in the art using a keyword database such as the US Patent and Trademark Office and trademark databases.

As it can be made feasible by skilled artisans, methods of synthesizing the compounds of the present formulas will be apparent to those of ordinary skill in the art, including the schemes and examples herein. In addition, the various synthetic steps may be carried out in an alternative step or to provide the desired compound. In addition, the solvent, temperature, reaction time, etc. of the present application are for illustrative purposes only and those of ordinary skill in the art will recognize changes in reaction conditions that can provide the desired compound of the present invention.

In addition, the compounds herein may comprise a bond (e. G., A carbon-carbon bond), wherein the bond rotation is limited with respect to a particular bond (e.g., due to the presence of a ring or double bond). Thus, all cis / trans and E / Z isomers are expressly included within the present invention. In addition, the compounds herein may be represented by a plurality of tautomeric forms, in which case the present invention explicitly encompasses all tautomeric forms described herein, even though they are expressed in one tautomeric form. All isomeric forms of the compounds herein are expressly included in the present invention. All crystal forms and polymorphs of the compounds described herein are expressly included in the present invention. Also included are extracts and fractions comprising the compounds of the invention. The term isomer includes diastereoisomers, enantiomers, regioisomers, structural isomers, rotamers, and tautomers. For compounds containing one or more stereogenic centers (e. G., Chiral compounds), the methods of the present invention may be carried out with mixtures of enantiomeric excess compounds, racemates, or diastereomers.

Preferred enantiomeric excess compounds are compounds having an enantiomeric excess of 50% or more, more preferably 60%, 70%, 80%, 90%, 95%, 98%, or 99% or more enantiomeric excess . In a preferred embodiment, only one enantiomer or diastereomer of the chiral compound of the invention is administered to the cell or subject.

Treatment method

In one aspect, the invention provides a method of treating a subject having or susceptible to a disorder or disease, comprising administering to the subject an effective amount of any one of the formulas (e.g., Formula I-XVII) A method of treating a subject suffering from.

In yet another aspect of the present invention, the present invention provides a method of treating a subject suffering from a metallothionein-related disease, comprising administering to a subject in need thereof an effective amount of any one of the compounds of the formulas (e. G., Formula I-XVII) A disorder or disease is treated, wherein the subject is one that requires treatment of a metal enzyme-related disorder or disease. ≪ RTI ID = 0.0 > .

In one aspect, the invention provides a method of treating a subject with a compound of any one of the present formulas (e.g., Formula I-XVII) in an amount sufficient to modulate a metalloenzyme activity under conditions sufficient to modulate a metal enzyme activity A method for regulating a metal enzyme activity of a cell in a subject,

In one embodiment, the modulation is inhibition.

In another aspect of the present invention, the present invention provides a method of treating a metal enzyme-related disorder, comprising administering to a subject an effective amount of any one of the formulas (e. G., Formula I-XVII) Or a method of treating a subject having or susceptible to disease.

In another aspect of the present invention, the present invention provides a method of treating or preventing a disease or condition comprising administering an effective amount of a compound or pharmaceutical composition of any one of the formulas (e. G., Formula I, Formula II, Formula III, A method of treating a subject having or susceptible to a metal enzyme-related disorder or disease, comprising administering to the subject a metal enzyme-related disorder or disease, wherein the subject is a metal enzyme-related disorder or disorder It is identified as requiring treatment of the disease.

In certain embodiments, the invention provides a method of treating a disease, disorder or symptom thereof, wherein said disorder is cancer, cardiovascular disease, inflammatory disease or infectious disease. In another embodiment, the disease, disorder or symptom thereof is a metabolic disease, an ophthalmic disease, a central nervous system (CNS) disease, a urological disease, or a gastrointestinal disorder. Specific examples of the disease include, but are not limited to, prostate cancer, breast cancer, inflammatory bowel disease, psoriasis, systemic fungal infection, skin structure fungal infection, mucosal fungal disease infection, onychomycosis, or superficial fungal infection.

In certain embodiments, the subject is a mammal, preferably a primate or a human.

In another embodiment, the present invention provides a method as described above wherein the effective amount of any one of the formulas herein (e. G., Formula I-XVII) is as described above.

In another embodiment, the present invention provides a method as described above wherein any one of the formulas (e.g., Formula I-XVII) herein is administered intravenously, intramuscularly, subcutaneously, intracerebrally, Or locally.

In another embodiment, the present invention provides a method as described above, wherein any one of the formulas herein (e.g., Formula I-XVII) shows selectivity for the activity range for the target enzyme For example, C. albicans MIC <1.0 μg / mL and A. fumigatus MIC <64 μg / mL).

In another embodiment, the present invention provides a method as described above wherein any one of the above formulas (e. G., Formula I-XVII) is administered alone or in combination with one or more other therapeutic agents. In yet another embodiment, the additional therapeutic agent is selected from the group consisting of an anti-cancer agent, an antifungal agent, a cardiovascular agent, an anti-infective agent, a chemotherapeutic agent, an antiangiogenic agent, a cytotoxic agent, an antiproliferative agent, a metabolic disease agent, CNS) disease therapeutic agent, a urological disease therapeutic agent, or a gastrointestinal disease therapeutic agent.

Another object of the present invention is the use of the compounds described herein (e. G., Of any of the formulas herein) in the manufacture of medicaments for the treatment of metal enzyme-related disorders or diseases. Another object of the present invention is the use of (for example, any of the formulas herein) compounds described herein for the treatment of metal enzyme-related disorders or diseases. Another object of the present invention is the use of (for example, any of the formulas herein) compounds described herein in the manufacture of an agricultural composition for the treatment or prevention of metal enzyme-related disorders or diseases in an agricultural or agricultural environment .

Pharmaceutical composition

In one aspect, the invention provides a pharmaceutical composition comprising a compound of any one of the formulas herein (e. G., Formula I-XVII) and a pharmaceutically acceptable carrier.

In another embodiment, the invention provides a pharmaceutical composition further comprising an additional therapeutic agent. In yet another embodiment, the additional therapeutic agent is selected from the group consisting of an anticancer agent, an antifungal agent, a cardiovascular agent, an anti-inflammatory agent, a chemotherapeutic agent, an antiangiogenic agent, a cytotoxic agent, an antiproliferative agent, ), A therapeutic agent for urinary diseases, or a therapeutic agent for gastrointestinal diseases.

In one aspect, the invention provides a method of treating a subject having or susceptible to a metal enzyme-related disease or disorder, including cancer, solid tumors, cardiovascular disease, inflammatory disease, infectious disease, A kit comprising an effective amount of any one of the formulas herein (e. G., Formula I-XVII) in the form of a dose. In another embodiment, the disease, disorder or symptom thereof is a metabolic disease, an ophthalmic disease, a central nervous system (CNS) disease, a urological disease, or a gastrointestinal disorder.

The term " pharmaceutically acceptable salt "or" pharmaceutically acceptable carrier "includes salts of the active compounds prepared with relatively non-toxic acids or salts according to the particular substituents present on the compounds described herein it means. When the compound of the present invention comprises a relatively acidic functional group, the base addition salt is obtained by contacting the neutral form of the compound with a sufficient amount of the desired base in neat or suitable inert solvent Can be. Examples of pharmaceutically acceptable base-addition salts include sodium salts, potassium salts, calcium salts, ammonium salts, organic amino salts, magnesium salts, or the like salts. When the compound of the present invention comprises a functional group that is a relatively basic acid-addition salt, it can be obtained by contacting the neutral form of the compound with a sufficient amount of the desired acid either neat or in a suitable inert solvent have. Examples of pharmaceutically acceptable acid addition salts include those derived from acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, but are not limited to salts derived from relatively non-toxic organic acids such as p-tolylsulfonic acid, citric acid, tartaric acid or methanesulfonic acid, as well as salts derived from relatively non-toxic organic acids such as hydrochloric acid, hydrobromic acid, nitric acid, But also salts derived from inorganic acids such as hydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, phosphorous acid and the like. Also included are salts of amino acids such as arginate and the like, salts of organic acids such as glucuronic acid or galacturonic acid (see, for example, Berge et al., Journal of Pharmaceutical Sciences 66: 1-19 (1977)). Any specific compound of the present invention includes both basic and acidic functionalities that allow the compound to be converted into a base- or acid-addition salt. Other pharmacologically acceptable carriers are known to those skilled in the art.

The neutral form of the compound can be produced by contacting the salt with a base or an acid and separating the parent compound in a known manner. The parent form of the compound differs from that of the various salts in the particular physical properties, such as solubility in polar solvents, although other salts may be equivalent to the parent form of the compound for the purposes of the present invention.

In addition to salt forms, the present invention provides compounds in prodrug form. Prodrugs of the compounds described herein are those compounds that are capable of readily carrying out chemical changes under physiological conditions to provide the compounds of the present invention. In addition, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when used as a transdermal patch reservoir with appropriate enzymes or chemical agents.

Certain compounds of the present invention may exist in unsolvated form as well as solvated forms including hydrated forms. Generally, the solvated form is equivalent to the unsolvated form and is included within the scope of the present invention. Certain compounds of the present invention may exist in a plurality of crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated in the present invention and are included within the scope of the present invention.

The invention also provides a pharmaceutical composition comprising an effective amount of a compound described herein and a pharmaceutically acceptable carrier. In one embodiment, the compound is administered to a subject for at least 12 hours, 24 hours, 36 hours, 48 hours, 1 week, 2 weeks after the administration of the pharmaceutically-acceptable agent, e.g., a pharmaceutically- Acceptable formulation that provides sustained delivery of the compound to the subject for about one week, three weeks, or four weeks prior to administration to the subject.

The actual dosage and time of administration of the active ingredient in the pharmaceutical composition of the present invention may be varied depending on the particular patient, composition, and method of administration so as to produce an effective effect to produce a desired pharmaceutical response without toxicity (or toxicity that is unacceptably toxic to the patient) Can be varied to obtain the amount of component.

In use, the at least one compound according to the invention is administered in a therapeutically effective amount to a subject in need thereof as a pharmaceutical carrier via intravenous, intramuscular, subcutaneous, or intracerebral injection or oral administration or topical application . According to the present invention, the compounds of the present invention may be administered alone or in combination with other secondary therapeutic agents. "In conjunction with" means at the same time, almost simultaneously or sequentially. In one embodiment, the compounds of the invention are administered acutely. Thus, the compounds of the present invention may be administered for short-term treatment, such as for about 1 day to about 1 week. In another embodiment, the compounds of the invention may be administered for a prolonged period of time, such as, for example, from about one week to several months, depending on the condition being treated, to ameliorate a chronic disorder.

"Therapeutically effective amount ", as used herein, is sufficiently high to significantly ameliorate symptoms within the scope of safe medical judgment and is sufficiently low (reasonable benefit / risk ratio) to avoid serious side effects, . The therapeutically effective amount of a compound of the present invention may vary depending on the age, the physical condition of the patient being treated, the severity of the potential disease, the duration of the treatment, the nature of the concurrent treatment, and the particular compound being applied, For example, the therapeutically effective amount of a compound of the present invention to be administered to an infant or a newborn baby can be suitably reduced according to safe medical judgment. Thus, a therapeutically effective amount of a compound of the present invention may be a minimal amount to provide a desired effect.

Certain practical advantages of the present invention are compounds that can be administered by a convenient route by intravenous, intramuscular, subcutaneous, oral, or intracerebral injection routes or by topical application such as creams or gels. Depending on the route of administration, the active component comprising the compound of the invention may be required to be coated to protect the compound from the action of enzymes, acids and other natural conditions capable of inactivating the compound. Unlike parenteral administration, for administration of the compounds of the present invention, the compounds may be coated with or otherwise administered with a material to protect against inactivation.

The compound can be administered orally or intraperitoneally. Dispersants may also be prepared, for example, in glycerol, liquid polyethylene glycols, and mixtures thereof, and in oils.

Some examples of materials that may be provided as pharmaceutical carriers include sugars such as lactose, glucose, and sucrose; Starches such as corn starch and potato starch; Cellulose, such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate, and derivatives thereof; Powdered tragacanth; malt; gelatin; Talc; Stearic acid; Magnesium stearate; Calcium sulfate; Vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and cacao tree oil; Polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; Agar; Alginic acid; Number of exothermic substances removed; Isotonic saline; And phosphate buffers; Skim milk powder; And compatible nontoxic substances for use in pharmaceutical preparations such as, for example, vitamin C, estrogens and Echinacea. In addition, wetting agents and lubricants such as sodium lauryl sulfate and coloring agents, flavoring agents, lubricants, excipients, refiners, stabilizers, antioxidants and preservatives may also be present. In addition, solubilizers such as cremaphore and beta -cyclodextrin may be used in the pharmaceutical composition of the present invention.

The pharmaceutical composition (or prodrug thereof) comprising an active compound of the disclosed subject matter of the present invention may be prepared by conventional means of mixing, dissolving, granulating, sugar-making powder, emulsifying, encapsulating, &Lt; / RTI &gt; The compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers, diluents, additives or adjuvants to promote the process of preparing the active compounds with the pharmaceutical preparations which may be used pharmaceutically.

The pharmaceutical compositions of the presently disclosed subject matter may be in a form suitable for administration of virtually any method, including, for example, topical, ocular, oral, buccal, rectal, nasal, injection, transdermal, rectal and vaginal, It may have a form suitable for administration via injection.

For topical administration, the active compound (s) or prodrug (s) may be formulated as solutions, gels, ointments, creams, suspensions, and the like.

Systemic formulations include those designed for administration, for example, subcutaneous, intravenous, intramuscular, intraspinal or intraperitoneal, and transdermal, transmucosal, oral, or pulmonary administration.

Useful injectable formulations include sterile suspensions, solutions or emulsions of the active compounds in water-soluble or oil vehicles. In addition, the compositions may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Formulations for injection may be prepared in unit dosage form (e.g., ampoules or multi-dose containers) and may contain additional preservatives.

Injectable formulations may also be presented in powder form for reconstitution prior to use with suitable vehicles, including, but not limited to, sterile pyrogen-free water, buffer, dextrose solution, and the like. To this end, the active compound may be reconstituted before drying and using, by any technique known in the art to which the present invention pertains, such as lyophilization.

For transmucosal administration, penetrants appropriate to penetrate the barrier into the formulation are used. Such penetrants are known in the art.

For oral administration, the pharmaceutical composition may contain a binder (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); Fillers (e. G., Lactose, microcrystalline cellulose or calcium hydrogen phosphate); Lubricants (e. G., Magnesium stearate, talc or silica); (For example, potato starch or sodium starch glycolate); Or in the form of lozenges, tablets or capsules prepared by conventional methods with pharmaceutically acceptable excipients such as wetting agents (e. G., Sodium lauryl sulfate). Tablets may be coated by, for example, sugar or enteric coatings by methods well known in the art to which the present invention pertains.

Liquid preparations for oral administration may take the form of, for example, elixirs, solutions, syrups or suspensions, or may be presented as a dried product for constitution with water or other suitable vehicle before use . The liquid formulation may contain a carrierizing agent (e. G., A sorbitol syrup, a cellulose derivative or a hardened edible oil); Emulsifiers (e. G., Lecithin or acacia); Water-insoluble vehicles (e. G., Almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); And preservatives (e. G., Methyl or propyl p-hydroxybenzoates or sorbic acid), in a conventional manner. The formulations may also contain suitable buffer salts, preservatives, flavoring agents, coloring agents and sweetening agents.

Formulations for oral administration may be suitably formulated to provide controlled release of the active compound or prodrug as is well known.

For oral administration, the compositions may have the form of tablets or lozenges formulated in conventional manner.

For rectal and vaginal route administration, the active compound (s) may be formulated as solutions, suppositories, or ointments (for rectal enema) comprising conventional suppository bases such as cocoa butter or other glycerides.

For administration by nasal administration or by inhalation or parenteral injection, the active compound (s) or prodrug (s) may be formulated with suitable compressed gases, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, Carbon, or other suitable gas in the form of an aerosol spray from a pressurized container or sprayer. With respect to the pressurized aerosol, the dosage can be determined by providing a valve for delivering the metered amount. Capsules or cartridges for use in an inhaler or insufflator (e.g., capsules and cartridges comprising gelatin) may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

Specific examples of aqueous suspension formulations suitable for nasal administration using commercially available nasal spray devices include the following: active compound or prodrug (0.5-20 mg / ml); Benzalkonium chloride (0.1-0.2 mg / mL); Polysorbate ^{80 (TWEEN ® 80; 0.5-5 mg} / ml); Carboxymethylcellulose sodium or microcrystalline cellulose (1-15 mg / ml); Phenylethanol (1-4 mg / ml); And dextrose (20-50 mg / ml). The pH of the final suspension can be adjusted in the range of about pH 5 to about pH 7, typically about pH 5.5.

For ocular administration, the active compound (s) or prodrug (s) may be formulated with solutions, emulsions, suspensions, and the like suitable for ocular administration. A variety of vehicles suitable for administering the compounds to the eye are known in the art. A specific non-limiting example is U.S. Pat. Patent No. 6,261,547; U.S.A. Patent No. 6,197,934; U.S.A. Patent No. 6,056,950; U.S.A. Patent No. 5,800,807; U.S.A. Patent No. 5,776,445; U.S.A. Patent No. 5,698,219; U.S.A. Patent No. 5,521,222; U.S.A. Patent No. 5,403,841; U.S.A. Patent No. 5,077,033; U.S.A. Patent No. 4,882,150; And U.S. Pat. Patent No. 4,738,851, each of which is incorporated herein by reference in its entirety.

For long-term delivery, the active compound (s) or prodrug (s) may be formulated as a depot for administration by subcutaneous or intramuscular injection. The active component may be prepared with a suitable polymer or hydrophobic material (such as, for example, an emulsifier in an acceptable oil) or an ion exchange resin, or an insoluble derivative such as, for example, a sparingly soluble salt. In addition, transdermal delivery systems can be used, in which an active compound (s), which is made up of an adhesive disk or patch and is absorbed into the skin, is slowly released. For this purpose, permeation enhancers can be used to promote transdermal penetration of the active compound (s). Examples of suitable transdermal patches are described in U.S. Pat. Patent No. 5,407,713; U.S.A. Patent No. 5,352,456; U.S.A. Patent No. 5,332,213; U.S.A. Patent No. 5,336,168; U.S.A. Patent No. 5,290,561; U.S.A. Patent No. 5,254,346; U.S.A. Patent No. 5,164,189; U.S.A. Patent No. 5,163,899; U.S.A. Patent No. 5,088,977; U.S.A. Patent No. 5,087,240; U.S.A. Patent No. 5,008,110; And U.S. Pat. Patent No. 4,921,475, each of which is incorporated herein by reference in its entirety.

In addition, other pharmaceutical delivery systems can be applied. Liposomes and emulsifiers are well known as examples of delivery vehicles that can be used to deliver the active compound (s) or prodrug (s). In addition, certain organic solvents such as dimethylsulfoxide (DMSO) may be applied.

The pharmaceutical composition may, if desired, be provided as a pack or drain device, which may include one or more unit dosage forms containing the active compound (s). For example, the pack may comprise a metal or plastic foil, such as a blister pack. The pack or draining device may include instructions for administration.

The active compound (s) or prodrug (s) of the disclosed subject matter or prodrug (s), or compositions thereof, will generally be administered in an amount effective to achieve the intended result, for example, an amount effective to treat or prevent the particular disease being treated Can be used. The compound (s) may be administered prophylactically to achieve a therapeutic or therapeutic effect to achieve a therapeutic effect. The therapeutic effect is meant to indicate an improvement in emotion or condition, even though the patient is still suffering from a baseline disease, such as a cure or improvement of the underlying disease and / or a cure or improvement of one or more symptoms associated with the underlying disease. For example, administration of a compound to a patient suffering from allergy may not only cure or ameliorate a basal allergic reaction, but also provide a therapeutic effect in which the severity or persistence of symptoms associated with allergies following a patient exposure to the allergen is reduced do. In another example, the therapeutic effect in asthma includes an improvement in respiration following the onset of asthma, or a decrease in the frequency or severity of asthma. In addition, the therapeutic effect includes preventing or slowing the progression of the disease, whether or not the improvement is perceived.

For administration for prophylaxis, the compound may be administered to a patient at risk of developing one of the diseases described above. Patients at risk for developing a disease can be patients who have the characteristics of a patient belonging to a risk group defined by the appropriate medical professional or the military. In addition, a patient at risk can be a patient in an onset condition of a basal condition that can generally or routinely be treated by administration of a metal enzyme inhibitor according to the present invention. In other words, a risk patient is a person who is exposed to a disease or illness in general or routinely, or can be exposed to acute exposure for a limited period of time. In addition, administration for prophylaxis may be applied to avoid the onset of symptoms in patients diagnosed with underlying diseases.

The amount of the compound administered will depend on a variety of factors including, for example, the particular indication being treated, the route of administration, whether the desired effect is prophylaxis or treatment, the severity of the indication being treated and the age and weight of the patient, It can depend on various factors. Determination of the effective dose can be understood by the ordinary skill of the artisan.

Effective doses can be measured initially from in vitro assays. For example, an initial dose for use in an animal may be determined to be an IC50 of or greater than the specific compound measured in vitro, such as an in vitro fungal MIC or MFC as described in the Example section, May be formulated to achieve blood or serum concentrations. The calculated dosages for achieving the circulating blood or serum concentrations, taking into account the bioavailability of a particular compound, may be understood by those of ordinary skill in the art. (See Fingl & Woodbury, "General Principles, " In: Goodman and Gilman ' s Pharmaceutical Basis of Therapeutics , Chapter 1, pp. 1-46, latest edition, Pagamonon Press,

In addition, the initial dose can be measured from in vivo data such as animal models. Animal models used to test the efficacy of compounds for treating or preventing the various diseases described above are well known in the art.

The dosage can generally be from about 0.0001 or 0.001 or from 0.01 mg / kg / day to about 100 mg / kg / day and may be increased or decreased depending, among other things, on bioavailability, route of administration and various factors mentioned above have. Effective amounts and dosing intervals may be adjusted individually to provide a plasma level of compound (s) sufficient to maintain a therapeutic or prophylactic effect. For topical administration or selective absorption, such as topical topical administration, the effective topical concentration of active compound (s) may not be related to plasma concentration. Conventional technicians can optimize local quantities without undue experimentation.

The compound (s) may be administered once a day, several times a day, or several times a day depending on the degree of cure and the judgment of the prescribing physician.

Preferably the compound (s) can provide a therapeutic or prophylactic effect without causing significant toxicity. The toxicity of the compound (s) can be determined using standard pharmaceutical procedures. The dose rate of toxic and therapeutic (or prophylactic) effects is the index of treatment. The compound (s) exhibiting a high therapeutic index is preferred.

The description of the list of chemical functional groups within the definition of any variable herein includes definitions of variables as any single functional group or combination of functional groups as defined. The description of the embodiments of the variables herein includes any single embodiment or combination of different embodiments or embodiments thereof as a part thereof. The description of the embodiments herein may include any single embodiment or embodiment as a different embodiment or a combination of parts thereof.

Agricultural application

The compounds and compositions herein may be used as a method of modulating the activity of metalloenzymes in plant microorganisms, including the contact of the compounds with plants (e. G., Seeds, seedlings, grasses, weeds, crops). The compounds and compositions herein may be used to treat plants, fields or other agricultural areas by administering (e.g., contacting, applying, spraying, spraying, salting) a compound or composition to a plant, field or other agricultural area of interest (For example, herbicides, pesticides, growth regulators, etc.). The administration may be carried out before germination or after germination. Administration may be effected for therapeutic or prophylactic use. The compositions and agricultural applications herein include lawns, lawns, landscaping gardens, home gardens, farms, grassland applications. Microorganisms can be present anywhere on a plant and include those described herein. The administration may be a method of treatment or prevention.

One aspect of the invention is a method of treating or preventing a fungal disease or disorder in a plant, comprising contacting the plant with a compound of any one of the formulas herein. Another aspect of the invention is a method of treating or preventing fungal growth in a plant or on a plant, comprising contacting the plant with a compound of any one of the formulas herein. Yet another aspect of the present invention is a method of inhibiting microorganisms in plants or plants, comprising contacting the plant with a compound of any one of the formulas herein.

Compositions comprising a compound of the present invention may be formulated into aqueous solutions, powders, suspensions, highly concentrated water-soluble, oil or other suspensions or dispersions, emulsifiers, oils, suspensions, emulsions or suspensions which can be sprayed, sprayed, sprayed, Dispersing agents, pastes, powders, pervious materials or granules.

Aqueous use forms may be prepared by adding water to emulsion concentrates, suspensions, pastes, wet powders or water-dispersible granules. Can be homogenized in water with a wetting agent, tackifier, oil treatment agent or emulsifier to produce a material that is soluble in an emulsifying agent, paste or oil dispersant, oil or solvent. However, it is possible to prepare a stock solution containing an active substance, a wetting agent, a tackifier, an oil treatment agent or an emulsifier and a suitable solvent or oil, and the stock solution is suitable to be diluted with water.

Granules, such as coated granules, deposited granules and homogenized granules, may be prepared by combining active ingredients (e.g., the compounds herein) with a solid carrier. The solid carrier may be selected from the group consisting of silica, silica gel, silicates, talc, kaolin, limestone, limestone, chalk, church clay, loess, clay, dolomite, diatomaceous earth, calcium sulfate, Fertilizers such as ammonium phosphate, ammonium nitrate, urea, and vegetable derived products such as grain flour, bark powder, sawdust and nutshell powder, cellulosic powder or other solid carriers.

The compounds may be formulated as general tablets, capsules, solids, liquids, emulsions, slurries, oils, granules or powders suitable for administration to plants, fields or other agricultural areas. In a preferred embodiment, the excipient is present in the carrier or diluent in an amount ranging from 1 to 95% (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 25%, 75% 90%, 95%) of the compounds of the present invention. The compositions described herein include compounds of the formulas described herein and additional agricultural formulations present in effective amounts to modulate (e.g., modulate, inhibit) a metal enzyme-related agricultural disease or disorder.

In one embodiment, the compound is provided as an encapsulated preparation (liquid or powder). Specific materials suitable for use as a capsule material include, but are not limited to, silica, perlite, talc, clay, pyrophyllite, diatomaceous earth, gelatine and gel, polymers (e.g., polyureas, polyurethanes, polyamides, G., Particulate, or porous particulate or material, such as cellulose. For example, hollow fibers, hollow tubes or tubing that emit compounds through the walls, capillary tubing that releases the compound out of the openings of the tubing, strips that release the compound out of the polymer substrate, , Another type of polymeric block such as a disc, a membrane system that holds the compound in an impermeable container and emits it through the measured permeable membrane, and combinations thereof. Examples of such dosage formulations are laminate polymers, polyvinyl chloride pellets, and microtubules.

The encapsulation process is generally classified chemically or mechanically. Examples of chemical processes for encapsulation include complex coacervation, polymer-polymer incompatibility, interfacial polymerization in liquid media, in situ polymerization, in-liquid drying, liquid But are not limited to, thermal and ionic gelation in media, desolvation in liquid media, starch-based chemical processes, trapping in cyclodextrin and production of liposomes. Examples of mechanical processes for encapsulation include spray drying, spray cooling, fluidized bed, electrostatic deposition, centrifugal extrusion, rotary disk or spin suspension separation, annular-jet encapsulation, liquid-gas or solid- Solvent evaporation, extrusion, or spraying into a solvent extraction vessel.

In addition, microcapsules are suitable for long term release of the active compounds herein. Microcapsules are small particles comprising a core material or active component surrounded by a coating or shell. The size of the microcapsules is generally from 1 to 1000 microns, and when the capsules are smaller than 1 micron, they are classified as nanocapsules, and when they are larger than 1000 microns, they are classified as macrocapsules. The core effective load is usually from 0.1 to 98% by weight. Microcapsules may have a variety of structures (continuous core / shell, polynuclear, or monolithic) and may have irregular or geometric shapes.

In another aspect, the compounds are provided in an oil-based delivery system. The oil release substrate includes plant and / or mineral oil. In one embodiment, the substrate comprises a surface activating agent such as a wetting agent, an emulsifying agent, and a dispersing agent to make the composition readily dispersible in water.

In addition, the compound of the present invention can be provided as an emulsifier. The emulsifying agent may be in the form of water-in-water (w / o) or water-in-oil (o / w). The droplet size can vary from nanometer size (colloidal dispersion) to hundreds of microns. A variety of surfactants and viscosity enhancers can be incorporated into the formulation for sizing droplets, emulsifying agent stabilization, and release adjustment.

In addition, the compounds of the present invention may be formulated as solid tablets and may be formulated as tablets or capsules containing active ingredients that are useful in the prevention or treatment of oil, protein / carbohydrate materials (preferably plant based), sweeteners and metal enzyme- (Preferably, but not necessarily). In one embodiment, the present invention provides a solid tablet comprising an active ingredient that is useful for the prevention or treatment of an oil, a protein / carbohydrate substance (preferably a plant based), a sweetener and a metal enzyme-related disease or disorder For example, the compounds or combinations or derivatives thereof). The tablets may be in the form of tablets or capsules which are usually prepared in the form of an oil (for example, corn, sunflower, ground, olive, grape seed, flowering tree, turnip, bean, cotton seed, walnut, palm, castor, almond, hazelnut, avocado, sesame, Vegetable oils such as rapeseed oil, canola oil and hydrogenated derivatives thereof, petroleum derived oils (e.g., paraffin and petroleum jelly), and hydrocarbons (such as paraffin) 40% by weight (e.g., 5%, 10%, 20%, 30%, 40%). In addition, the tablets generally comprise about 5-40% (e.g., 5%, 10%, 20%, 30%, 40%) of the plant-based protein / carbohydrate material. The material may be selected from carbohydrate moieties (e.g., wheat, rye, barley, oats, corn, rice, millet, sorghum, birdseed, buckwheat, Bran, corn gluten meal, algae powder, dry yeast, soybeans, rice) and protein portions.

Alternatively, various excipients and binders may be used to assist in the delivery of the active ingredient or to provide a suitable structure of the tablet. Preferred excipients and binders include anhydrous lactose, microcrystalline cellulose, corn starch, magnesium stearate, calcium estersate, zinc stearate, sodium carboxymethylcellulose, and mixtures thereof. Treatment, or prevention. In one embodiment, the kit comprises a composition comprising an effective amount of a compound of the present invention in a form suitable for delivery to a plant part. In some embodiments, the kit comprises a container comprising a compound of formula (I); The container may be in the form of a box, ampoule, bottle, vial, tube, bag, pouch, blister pack or other suitable container known in the art. The container may be made of plastic, glass, a laminate, a metal foil or any other suitable material for fixing the compound.

If desired, the compound (s) of the present invention are provided with instructions for administration to a plant, field or other agricultural area. The description generally includes information regarding the use of the composition to treat or prevent a metal enzyme-related agricultural disease or disorder. In another embodiment, the instructions comprise at least one of the following: a component of the compound; Dosing schedule and dosage for treating or preventing a metal enzyme-related agricultural disease or disorder; Precautions; warning; Summary of Research Results; And / or references.

The instructions may be in the form of a label printed directly on the container (if present) or applied to the container, or as a separate sheet, pamphlet, card, or folder provided with or in the container.

Example

The present invention will be described using specific embodiments, but it is not necessarily construed as being limited thereto.

General experimental procedure

The definitions of the variables of the structures in the present scheme correspond to the corresponding positions in the formulas described herein.

Synthesis of Azol

Synthesis of the alkaline target (III) can be achieved using the synthesis of the examples shown below.

A wide range of substituted phenyl analogs can be prepared starting from an aryl-bromide starting material (e. G., 13). The synthesis of an example of target (III) is the condensation of copper-activated ethyl alpha -bromo-acetate with ethyl 2,5-dibromo-pyridine, the lithiated bromodifluorobenzene and the initial ethyl ester product Condensation to generate ketone C (Scheme 1). The ketone is epoxidized with diazomethane and then converted to trimethylsilyl (TMS) -acetylide K to provide the epoxide J. TMS-acetylide K is converted to stenyl-acetylide M via a desilylated epoxide L. Stenyl-acetylide M is then coupled with a variety of bromophenyl moieties to provide a disubstituted acetylenic intermediate (e. G., N). The corresponding 1-tetrazole product (e.g., 13) (and the 2-tetrazole isomer) is obtained by opening the corresponding disubstituted acetylene epoxide intermediate (e.g., N).

Scheme 1

In an embodiment, the present invention provides intermediate compounds of the formulas described herein and methods of converting such compounds to compounds of the formulas described herein (including one or more chemical modifications (including those provided herein) And one or more reagents) to provide any compound of the formula described herein and its intermediate compounds.

The synthetic methods described herein may also include additional steps to add or remove suitable protecting groups before or after any step described in any of the reaction schemes to ultimately synthesize compounds of the formulas described herein. The methods described herein contemplate the conversion of one formula compound into another. This conversion process refers to one or more chemical modifications, which may be performed in situ , or by separation of an intermediate compound.

Modifications can include reacting a starting compound or intermediate with an additional reagent using techniques and protocols known in the art, including references cited herein. The intermediates can be used with or without purification (for example, filtration, distillation, sublimation, crystallization, trituration, solid phase extraction, and chromatography).

Ketone C

Ethylbromodifluoroacetate (2.70 mL, 21.10 mmol) was added to a copper powder suspension (2.68 g, 42.2 mmol) in DMSO (35 mL) and the resulting mixture was stirred at room temperature for 1 h. Then 2,5-dibromopyridine A (2.50 g, 10.55 mmol) was added and stirred continuously at room temperature for 15 h. The reaction was quenched with aqueous NH ₄ Cl (aqueous NH ₄ Cl) and extracted with DCM (3 x 25 mL). The combined organic layers were washed with water, was washed with brine (brine), was dried over anhydrous Na ₂ SO _4, concentrated under reduced pressure, and was provided The crude product mixture (crude product mixture), which purification column with EtOAc / hexane Ethyl ester intermediate B (2.40 g, 8.57 mmol, 81%) was obtained as a pale yellow oil. ^{1 H NMR (500 MHz, CDCl} 3): δ 8.71 (s, 1 H), 8.00 (d, J = 9.0 Hz, 1 H), 7.64 (d, J = 9.0 Hz, 1 H), 4.42-4.35 ( m, 2 H), 1.39-1.31 (m, 3 H).

N -Butyl lithium (3.70 mL, 8.57 mmol) was added to a stirred solution of 2,4-difluoro-bromobenzene (1.65 g, 8.57 mmol) in diethyl ether (10 mL) Minute, ester B (2.40 g, 8.57 mmol) in diethyl ether (5 mL) was added. The reaction mixture was stirred at -70 &lt; 0 &gt; C for 1 h, warmed to ambient temperature and stirred at this temperature for an additional 2 h. The reaction was terminated with aqueous NH ₄ Cl solution and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with water, was washed with brine, was dried over anhydrous Na ₂ SO _4, was concentrated under reduced pressure. The crude compound was purified by column chromatography to provide the ketone C as a yellow liquid. ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.62 (s, 1H), 8.08-8.04 (m, 2H), 7.74-7.70 (m, 1H), 7.05-6.95 6.88-6.78 (m, 1H). MS (ESI): 347, 349 [(M ⁺ +1) ^&lt; + 2 &gt;].

Example 13

Ethynyl) pyridin-2-yl) -2- (2,4-di (tert-butyldimethylsilyloxy) Fluorophenyl) -1,1-difluoro-3- (1H-tetrazol-1-yl) propan-

Preparation of 4 - ((4-bromophenoxy) methyl) benzaldehyde (F).

Potassium carbonate (0.631 g, 4.57 mmol) and 4- (bromomethyl) benzaldehyde (0.500 g, 2.51 mmol) were added to a solution of 4-bromophenol (0.395 g, 2.28 mmol) in N , N- dimethylformamide ) Were continuously added.

The yellow suspension was then heated in an oil bath at &lt; RTI ID = 0.0 &gt; 80 C &lt; / RTI &gt; for 1 h. The reaction was then terminated with water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine (10 mL), dried (Na ₂ SO ₄ ), filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by chromatography (silica gel; gradient elution with hexane / ethyl acetate in hexane to 80:20) to give 4 - ((4-bromophenoxy) methyl) benzaldehyde and provided (F, 0.568 g, 86% ): 1 H NMR (300 MHz, CDCl 3) δ 10.02 (s, 1H), 7.90 (d, J = 8.1 Hz, 2H), 7.58 (d, J = 8.0 Hz, 2H), 7.42-7.35 (m, 2H), 6.88-6.81 (m, 2H), 5.12 (s, 2H).

(4 - ((4-bromophenoxy) methyl) phenyl) methanol (G).

Sodium borohydride (0.069 g, 1.82 mmol) was treated with a suspension of 4 - ((4-bromophenoxy) methyl) benzaldehyde ( F , 0.482 g, 1.66 mmol) in ethanol (20 mL) at -10 ° C. The reaction mixture was slowly warmed to &lt; RTI ID = 0.0 &gt; 10 C &lt; / RTI &gt; over 45 minutes before quenching with aqueous ammonium chloride solution. The mixture was then diluted with brine and extracted with dichloromethane (3 x 30 mL). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by chromatography (silica gel; gradient elution with 50:50 hexane / ethyl acetate in hexane) to give (4 - ((4-bromophenoxy) methyl) Phenyl) methanol ( G , 0.476 g, 96%): ¹ H NMR (300 MHz, CDCl ₃ )? 7.45-7.30 (m, 6H), 6.88-6.79 (m, 2H), 5.03 ), 4.70 (d, J = 5.9 Hz, 2H), 1.71 (t, J = 5.9 Hz, 1H).

Preparation of 4 - ((4-bromophenoxy) methyl) benzyl methanesulfonate (H).

To a solution of (4 - ((4-bromophenoxy) methyl) phenyl) methanol ( G , 1.15 g, 3.92 mmol) in dichloromethane (36 mL) at 0 ° C was added N , N -diisopropylethylamine , 4.31 mmol) was added followed by methanesulfonyl chloride (0.495 g, 4.31 mmol). The mixture was stirred at 0 &lt; 0 &gt; C for 15 min, allowed to warm to ambient temperature and stirred at ambient temperature for 3 h. The solvent was then evaporated under reduced pressure and the residue was further dried under vacuum at 40 ^° C to give 4 - ((4-bromophenoxy) methyl) benzyl methanesulfonate ( H , 1.40 g, 96% and ^{provided: 1 H NMR (300 MHz,} CDCl 3) δ 7.40-7.35 (m, 6H), 6.84 (dd, J = 6.9, 2.1 Hz, 2H), 5.30 (s, 2H), 5.03 (s, 2H ), 2.81 (s, 3H). δ7.40-7.35 (m, 6H), 6.84 (dd, J = 6.9, 2.1 Hz, 2H), 5.30 (s, 2H), 5.03 (s, 2H), 2.81 (s, 3H).

Preparation of 1- (4 - ((4-bromophenoxy) methyl) benzyl) -1 H-pyrazole (I).

To a solution of 4 - ((4-bromophenoxy) methyl) benzyl methanesulfonate ( H , 1.45 g, 3.90 mmol) in DMF (5 mL) at room temperature was added 1 H- pyrazole (0.320 g, 4.68 mmol) Carbonitrile (1.52 g, 4.68 mmol) was added. The mixture was mixed at 70 DEG C for 1 h. The reaction was then cooled to room temperature and the solvent was evaporated under reduced pressure. The residue obtained was diluted with water (40 ml) and extracted with ethyl acetate (3 x 100 ml). The combined extracts were washed with brine (40 mL), dried (Na ₂ SO ₄ ), filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by chromatography (silica gel; hexane / ethyl acetate in hexane to 60:40 gradient elution). The product was then purified by a second chromatography (silica gel; dichloromethane, isocratic elution) to give 1- (4 - ((4-bromophenoxy) methyl) benzyl) -1 H - pyrazole provided the (I, 0.150 g, 11% ): 1 H NMR (300 MHz, CDCl 3) δ 7.54 (d, J = 1.8 Hz, 1H), 7.37-7.32 (m, 5H), 7.21 ( (d, J = 8.1Hz, 2H), 6.84-6.79 (m, 2H), 6.27 (t, J = 2.4Hz, 1H), 5.32 (s, 2H), 4.98

Preparation of 5-bromo-2 - ((2- (2,4-difluorophenyl) oxiran-2-yl) difluoromethyl) pyridine (J).

Tetrahydrofuran (142 mL) and DMSO (85 mL) for 10 ℃ within trimethylsulfonium LOL iodide (10.73 g, 48.75 mmol) of potassium tert in solution - 20% by weight in butoxide (THF, 30.47 mL, 48.75 mmol ) Were processed. After the addition was complete, the mixture was warmed to room temperature and stirred for 1.5 h. The mixture was then cooled to -10 ° C and a solution of 2- (5-bromopyridin-2-yl) -1- (2,4-difluorophenyl) -2,2-difluoro Ethanone ( C , 14.14 g, 40.62 mmol) dropwise over a period of 5-10 minutes. After stirring at -10 [deg.] C for 1 h, water was added and the mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by chromatography (silica gel; gradient elution with hexane / ethyl acetate in hexane to 95: 5) to give 5-bromo-2 - ((2- (2, Yl) difluoromethyl) pyridine ( J , 10.71 g, 61%) as a white solid: ¹ H NMR (300 MHz, CDCl ₃ )? 8.72 (d, J = 1.9 Hz , 1H), 7.89 (dd, J = 8.4, 2.3 Hz, 1H), 7.47-7.31 (m, 2H), 6.92-6.80 (m, 1H), 6.74 (dt, J = 4.8, 2.3 Hz, 1H), 3.44 (d, J = 5.0 Hz, 1 H), 3.02 - 2.92 (m, 1 H).

Preparation of 2 - ((2- (2,4-difluorophenyl) oxiran-2-yl) difluoromethyl) -5 - ((trimethylsilyl) -ethynyl) pyridine (K).

To a solution of 5-bromo-2- ((2- (2,4-difluorophenyl) oxiran-2-yl) difluoromethyl) pyridine ( J , 10.00 g, 27.62 mmol) in tetrahydrofuran mmol), copper (I) iodide (0.263 g, 1.38 mmol) and dichlorobis (triphenylphosphine) palladium (II) (0.965 g, 1.37 mmol, ) And triethylamine (10 mL) were added. The mixture was stirred at ambient temperature for 16 h before being filtered through a Celite plug. The plug was rinsed with ethyl acetate and the filtrate was washed with water (100 mL) and brine (100 mL). The organic layer was dried (Na ₂ SO _4), was filtered off, the filtrate was concentrated under reduced pressure. The resulting crude was purified by chromatography (silica gel; hexane / ethyl acetate in hexane to hexane / ethyl acetate; gradient elution) to afford 2 - ((2- (2,4 ( K , 10.01 g, 96%) as a colorless oil: ¹ H NMR (300 MHz, CDCl _3, ) δ 8.69 (s, 1H) , 7.78 (dd, J = 8.1, 1.9 Hz, 1H), 7.41 (dd, J = 8.1, 0.6 Hz, 1H), 7.34 (q, J = 7.7 Hz, 1H), 6.87 1H), 6.72 (dt, J = 4.7, 2.2 Hz, 1H), 3.45 (d, J = 5.0 Hz, 1H), 3.01-2.93 (m, 1H), 0.28 (s, 9H).

2 - Preparation of ((2- (2,4-difluorophenyl) oxiran-2-yl) methyl-difluoro) carbonyl-5-ethynyl pyridine (L)

(2- (2,4-difluorophenyl) oxiran-2-yl) difluoromethyl) -5- ((trimethylsilyl) ethynyl) -pyridine in 111 mL of tetrahydrofuran ( K , 10.00 g, 26.36 mmol) was treated with 1 M TBAF in tetrahydrofuran (29.0 mL, 28.99 mmol) and added drop wise over 15 min.

After stirring at -10 ° C to -5 ° C for 30 minutes, the volatiles were removed under reduced pressure at a bath temperature of 10 ° C or lower. The residue obtained was redissolved in ethyl acetate (250 mL) and washed with water (100 mL) and brine (100 mL). The organic layer was dried (Na ₂ SO _4), was filtered off, the filtrate was concentrated under reduced pressure. The residue obtained was purified by chromatography (silica gel; gradient elution with hexane / ethyl acetate in hexane to 95: 5) to give 2 - ((2- (2,4-difluorophenyl ) oxiran-ethynyl -2-yl) methyl-difluoro) pyridin-5 (L, 6.47 g, was enhanced to ^{80%): 1 H NMR (} 300 MHz, CDCl 3) δ 8.74 (d, J = 1.0 Hz 1H), 7.83 (dd, J = 8.1, 1.9 Hz, 1H), 7.45 (d, J = 8.2 Hz, 1H), 7.41-7.31 6.69 (m, 1H), 3.45 (d, J = 5.0 Hz, 1H), 3.31 (s, 1H), 3.02-2.94 (m, 1H).

Preparation of 2 - ((2- (2,4 -difluorophenyl ) oxiran -2-yl) difluoromethyl ) -5 - (( tributylstannyl ) -ethynyl) pyridine (M).

( L- (2,4-difluorophenyl) oxiran-2-yl) difluoromethyl) -5-ethynylpyridine (33 mg) in diethyl ether (33 mL) 1.50 g, 4.88 mmol) in THF (20 mL) was treated dropwise with 2.5 M n -butyllithium in hexane (2.35 mL, 5.88 mmol). The mixture was stirred at -78 [deg.] C for 45 minutes before tributylchlorostannane (1.99 mL, 7.34 mmol) was added. The mixture was slowly warmed to ambient temperature over 15 h before being quenched with aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate (2 x 25 mL) and the combined extracts were washed with water (25 mL) and brine (25 mL). The organic layer was dried (Na ₂ SO ₄ ), filtered and the filtrate was concentrated under reduced pressure to give a yellow syrup (Crude weight: 4.06 g). Methyl) -5 - ((tributylstannyl) ethynyl) pyridine ( M ) can be prepared by reacting a crude 2 - [(2- (2,4- difluorophenyl) oxiran- It was used without further purification.

5 - ((4 - (( 4 - ((1H- pyrazol-1-yl) methyl) benzyl) oxy) phenylethynyl)) 2 - ((2- (2,4-difluorophenyl) oxirane -2-yl) difluoromethyl) pyridine (N).

( M , est. 0.472 mmol) of 2 - ((2,4- difluorophenyl) oxiran-2-yl) difluoromethyl) -5 - ((tributylstannyl) de (crude) samples successively 1,4-dioxide hexanes (2 mL) and 1- (4 - ((4-bromo-phenoxy) methyl) benzyl) -1 H-pyrazole (0.135 g, 0.393 mmol ) Was added. The reaction mixture was sparged with argon for 20 minutes before adding tetrakis (triphenylphosphine) palladium (0) (0.054 g, 0.047 mmol). The mixture was sprayed with argon for an additional 20 minutes before heating at 80 &lt; 0 &gt; C for 3 h. The mixture was then concentrated under reduced pressure and chromatographed (silica gel, gradient elution with hexane / ethyl acetate in hexane 60:40) to give 5 - ((4 - ((4 - ((1 H-pyrazol-1-yl) methyl) benzyl) oxy) phenyl) ethynyl) -2 - ((2- (2,4-difluorophenyl) oxy-carbonyl-2-yl) methyl-difluoro ) Pyridine ( N , 0.141 g). Crude was used without further purification.

1- (5 - ((4 - ((4 - ((1 H - pyrazol-1-yl) methyl) benzyl) oxy) phenylethynyl)) pyridin-2-yl) -2- (2, Difluorophenyl) -1,1-difluoro-3- ( 1H -tetrazol-1-yl) propan-2-ol (13).

N, N - dimethylformamide - amide (4 mL) in a 5 Crude - ((4 - ((4 - ((1H- pyrazol-1-yl) methyl) benzyl) oxy) phenylethynyl)) - 2 - ((2- (2,4-difluorophenyl) oksilran-2-yl) methyl-difluoro) pyridine (N, 0.155 g) 1 H continuous solid solution-tetrazol (0.120 g, 1.71 mmol) and potassium Carbonate (0.057 g, 0.408 mmol) was added. The mixture was heated at 65 [deg.] C for 44 h. Water (10 mL) was then added and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by chromatography (silica gel; ethyl acetate in hexanes; gradient elution). The resulting product was subjected to a second chromatography under reversed phase conditions (C18; water / acetonitrile in water at 40:60; gradient elution) and lyophilized with water / acetonitrile to give 1 - (5 - ((4 - ((4 - ((1 H - pyrazol-1-yl) methyl) benzyl) oxy) phenylethynyl)) pyridin -2-yl) -2- (2,4- difluorophenyl) -1,1-difluoro -3- (1 H - to give the tetrazol-1-yl) propan-2-ol (13, 0.082 g, 33% two steps): mp 179-184 ^o C; ^{1 H NMR (300 MHz, CDCl} 3) δ 8.76 (s, 1H), 8.62 (d, J = 1.3 Hz, 1H), 7.86 (dd, J = 8.2, 1.9 Hz, 1H), 7.56 (dd, J = 2H), 7.43-7.37 (m, 4H), 7.34-7.26 (m, 1H), 7.24 (d, J = 8.2 Hz, 1H) , J = 8.2 Hz, 2H) , 6.99-6.92 (m, 2H), 6.76 (ddd, J = 11.9, 8.6, 2.6 Hz, 1H), 6.70-6.62 (m, 1H), 6.29 (t, J = 2.1 Hz, 1 H), 5.62 (d, J = 14.3 Hz, 1H), 5.34 (s, 2H), 5.15-5.05 (m, 3H); MS (ESI) m / z 640 [M + H] &lt; ⁺ &gt;;HPLC> 99% (AUC), t R 20.74 min (Method B).

Examples 1-12 and 14-16 were essentially prepared according to the synthetic procedure above. The following table contains the compound information and analysis data of Examples 1-16.

Examples 17-86 can be synthesized using the specified synthetic methodology of Example 13 .

Method A:

Column, Type, Size

Sunfire C-18 (150 X 4.6 mm, 5 탆)

Mobile Phase A: Mobile Phase A: MeCN

Mobile phase B: Mobile Phase B: 50 mM NH 4 HCO2

Flow Rate Flow Rate: 1.0 mL / min

Method B:

Column, Type, Size

Phenomenex Luna C-18 (150 X 4.6 mm, 5 [mu] m)

Mobile Phase A: Mobile Phase A: MeCN w / 0.1% TFA

Mobile Phase B: Mobile Phase B: Water w / 0.1% TFA

Flow Rate Flow Rate: 1.0 mL / min

Example 87: Metal enzyme activity

A. Minimum inhibitory concentration (MIC)

Compounds were evaluated in inhibiting the growth of common lines (common strains) of using the standardized procedures (CLSI M27-A2) fungus C. albicans (C. albicans) efficacy.

Test stock solution (Stock solutions) of the compound and a standard (standards) was prepared in DMSO in 1600 ㎍ / mL C. albicans (C. albicans). Eleven sequential 1/2 diluted compounds were prepared in 96 well plates of RPMI + MOPS. The assay range was 1 - 0.001 ㎍ / mL ( C. albicans ). C. Albikans Cell suspensions were prepared at a concentration of about 3.7 X 10 ³ colony-forming-units (cfu / mL) and added to each well. All tests were performed twice. Duplicate inoculated plates were incubated at 35 ± 1 ° C for approximately 48 h. Upon completion of incubation, the wells of each plate at completion were evaluated visually for the presence of fungal growth.

The MIC, with proponazole and test compounds, is a concentration at which growth is significantly reduced (about 50% reduction). The MIC of voriconazole is the concentration at which the C. albicans growth is reduced by 50% (CLSI, M27-A2). For QC purposes, C. represent krusei (C. krusei) isolated strain ^{ATCC 6258 (4.0 X 10 3 cfu} / mL) was included to separate the VOR black fungus growth tailing (trailing growth) for voriconazole And thus the MIC was the concentration at which the growth was completely inhibited.

A. The fumigatus MIC is determined at 50% and 100% growth inhibition in the concentration range of 64 - 0.062 μg / mL (CLSI M38 - A2) according to the following CLSI guidelines.

The compounds were isolated from their &lt; RTI ID = 0.0 &gt; Coxidioides &lt; The growth inhibitory effects of Posada when (Coccidioides posadasii) was evaluated.

C. is clinically separated from one system Posada during the patient's (C. posadasii, silberiah system (Silveira strain)) were selected for the test. Siberia is a common strain maintained and used in research laboratories. The lines were grown and harvested on GYE agar plates and arthroconidia for maturation.

Segment spores were adjusted to a final concentration of viable spores (colony forming units or CFU) of 0.4-5.0 X 10 ⁴ per milliliter in glucose yeast extract broth. The number of CFU was verified by dilution and enumeration on glucose yeast extraction plates. The inoculum was visually apparent.

The stock solution of the test compound was diluted as previously described in DMSO and added to the liquid medium at the final concentration of 1% DMSO by inoculation. A double dilution between 0.06 ug / ml and 2 ug / ml was assayed; Pruronazole was used as a comparator under a double dilution between 16 ug / ml and 128 쨉 g / ml. Pruronazole was water soluble, but was also tested in 1% DMSO, so media conditions were the same in all wells.

After incubation at 37 ° C for 48 h, compound dilutions were visually compared to control tubes and turbidity. The turbidity of the control tube was measured, and the indicated concentration represents a 50% inhibition of fungal growth. Growth inhibition was assayed between 0.06 ug / ml and 2 ug / ml.

The compounds of the present invention inhibit the growth of Coccidioides posadasii. For example, both compounds 5 and 7 showed MIC-50 at 0.12 ug / mL.

Results: Antimicrobial activity

_{* Candida Albikans MIC50 (median inhibitory concentration) ug / mL; &lt; / RTI &gt; Aspergillus MIC50  shame} ^{Was expressed in ug / mL.}

Included in references.

 The contents of all references cited herein (including articles, patent registration publications, patent publications and pending patent applications) are expressly incorporated herein by reference.

Equivalent

Those skilled in the art will recognize numerous equivalents of the specific embodiments of the invention disclosed herein or may be able to ascertain it without repeated experimentation. Such equivalents are intended to be included in the claims.

Claims (58)

A compound of formula (XVI), or a salt thereof, wherein:

R &lt; ₁ &gt; is fluorine;
R ₂ is fluorine;
Each R &lt; ₄ &gt; is independently aryl substituted with 0, 1, 2 or 3, independent R &lt; ₈ &gt;;
R ₅ is H, alkyl, phosphato, phosphito, alkoxy phosphato, or -C (O) alkyl optionally substituted with 1 or 2 amino;
Each R &lt; ₈ &gt; is independently optionally substituted alkyl, cyano, haloalkyl, alkoxy, halo, or haloalkoxy;
Each R &lt; ₃₅ &gt;

,

,

,

,

, or

ego;
Each X is independently O or S;
Each Y is independently OH, NH _2, or NH-SO ₂ -R _17, and;
Each n is independently 1, 2, or 3;
Each o is independently 0, 1, 2, or 3;
Each p is independently 0, 1, 2, or 3;
Each t is independently 0, 1, 2, or 3;
Each R &lt; ₁₄ &gt; is independently:
a) 1, 2, or 3 independent OH, haloalkoxy, optionally substituted heterocyclo, optionally substituted heteroaryl,

,

,

,

,

,

, or

&Lt; / RTI &gt;
b) an independent OR ₁₇ of 0, 1, 2, or 3; or

&Lt; / RTI &gt;
c)

; or
d) optionally substituted heterocyclo;
Each R ₃₂ is independently:
a) haloalkyl;
b) halo;
c) 0, 1, 2, or 3 independent OH, haloalkoxy, optionally substituted heterocyclo, optionally substituted heteroaryl,

,

,

,

,

, or

&Lt; / RTI &gt; or
d)

ego;
Each R &lt; ₁₆ &gt; is independently:
a) 0, 1, 2, or 3 independently substituted aralkyl:
(1) cyano;
(2) halo;
(3)

;
(4) alkoxy;
(5) haloalkyl;
(6) haloalkoxy;
(7) optionally substituted alkyl;
(8) optionally substituted aryl;
(9) optionally substituted heteroaryl; or
(10) optionally substituted heterocyclyl;
b) OR ₁₇ ; or
c) optionally substituted aryl;
Each R &lt; ₁₇ &gt; is independently H, optionally substituted alkyl, haloalkyl, or

to be.
Each R &lt; ₁₈ &gt; is independently:
a) independently substituted 0, 1, 2, or 3 aryl:
(1) halo;
(2) haloalkyl;
(3) alkoxy;
(4) haloalkoxy;
(5) optionally substituted cycloalkyl;
(6) optionally substituted heterocyclyl;
(7) optionally substituted alkyl;
(8)

;
(9) OR ₁₉ ;
(10) SR ₁₉ ;
(11) optionally substituted heteroaryl; or
(12) cyano;
b) optionally substituted cycloalkyl;
c) optionally substituted heteroaryl;
d) optionally substituted heterocyclyl;
e) optionally substituted alkyl;
f) optionally substituted cycloalkylalkyl;
g) optionally substituted cycloalkylalkoxy;
h) haloalkyl;
i) haloalkoxy;
j) haloalkoxyalkyl;
k)

; or
l) an optionally substituted aralkyl;
Each R &lt; ₁₉ &gt; is independently H, optionally substituted alkyl, or haloalkyl;
Each R &lt; ₂₀ &gt; is independently H, optionally substituted alkyl, or

ego;
Each R &lt; ₃₃ &gt; is independently H, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkylcarbonyl, or

ego;
Each R &lt; ₂₂ &gt; is independently:
a)

;
b) optionally substituted alkyl;
c) optionally substituted aryl;
d) optionally substituted heteroaryl;
e) optionally substituted cycloalkyl; or
f) optionally substituted heterocyclyl; And
Each R &lt; ₂₅ &gt; is independently optionally substituted aryl; Optionally substituted arylalkyl, haloalkoxy, (haloalkoxy) alkyl, cycloalkyl, _{alkyl, -CH 2 CF 2 CF 3,} -CF 2 CF 3, or

/ RTI &gt; A compound of formula (VII), or a salt thereof, wherein:

R &lt; ₁ &gt; is halo;
R ₂ is halo;
Each R ₂₇ is independently alkyl, cycloalkyl, or aralkyl each of which is substituted with 0, 1, 2 or 3, independent R ₈ ;
R ₅ is H, alkyl, phosphato, phosphito, alkoxy phosphato, or -C (O) alkyl optionally substituted with 1 or 2 amino;
Each R &lt; ₈ &gt; is independently optionally substituted alkyl, cyano, haloalkyl, alkoxy, halo, or haloalkoxy;
Each R &lt; ₃₀ &gt;

,

,

,

,

, or

ego;
Each X is independently O or S;
Each Y is independently OH, NH _2, or NH-SO ₂ -R _17, and;
Each n is independently 0, 1, 2, or 3;
Each o is independently 0, 1, 2, or 3;
Each p is independently 0, 1, 2, or 3;
Each t is independently 0, 1, 2, or 3;
Each R &lt; ₃₁ &gt; is independently:
a) 1, 2, or 3 independent OH, haloalkoxy, optionally substituted heterocyclo, optionally substituted heteroaryl,

,

,

,

,

,

, or

&Lt; / RTI &gt;
b) an independent OR ₁₇ of 0, 1, 2, or 3; or

&Lt; / RTI &gt;
c)

;
d) halo;
e) haloalkyl;
f) haloalkoxy; or
g) optionally substituted heterocyclo;
Each R ₃₂ is independently:
a) haloalkyl;
b) halo;
c) 0, 1, 2, or 3 independent OH, haloalkoxy, optionally substituted heterocyclo, optionally substituted heteroaryl,

,

,

,

,

, or

&Lt; / RTI &gt; or
d)

; or
e) haloalkoxy;
Each R &lt; ₁₆ &gt; is independently:
a) 0, 1, 2, or 3 independently substituted aralkyl:
(1) cyano;
(2) halo;
(3)

;
(4) alkoxy;
(5) haloalkyl;
(6) haloalkoxy;
(7) optionally substituted alkyl;
(8) optionally substituted aryl;
(9) optionally substituted heteroaryl; or
(10) optionally substituted heterocyclyl;
b) OR ₁₇ ; or
c) optionally substituted aryl;
Each R &lt; ₁₇ &gt; is independently H, optionally substituted alkyl, haloalkyl, or

ego,
Each R &lt; ₁₈ &gt; is independently:
a) independently substituted 0, 1, 2, or 3 aryl:
(1) halo;
(2) haloalkyl;
(3) alkoxy;
(4) haloalkoxy;
(5) optionally substituted cycloalkyl;
(6) optionally substituted heterocyclyl;
(7) optionally substituted alkyl;
(8)

;
(9) OR ₁₉ ;
(10) SR ₁₉ ;
(11) optionally substituted heteroaryl; or
(12) cyano;
b) optionally substituted cycloalkyl;
c) optionally substituted heteroaryl;
d) optionally substituted heterocyclyl;
e) optionally substituted alkyl;
f) optionally substituted cycloalkylalkyl;
g) optionally substituted cycloalkylalkoxy;
h) haloalkyl;
i) haloalkoxy;
j) haloalkoxyalkyl;
k)

; or
l) an optionally substituted aralkyl;
Each R &lt; ₁₉ &gt; is independently H, optionally substituted alkyl, or haloalkyl;
Each R &lt; ₂₀ &gt; is independently H, optionally substituted alkyl, haloalkyl, or

ego;
Each R &lt; ₃₃ &gt; is independently H, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkylcarbonyl, or

ego;
Each R &lt; ₂₂ &gt; is independently:
a)

;
b) optionally substituted alkyl;
c) optionally substituted aryl;
d) optionally substituted heteroaryl;
e) optionally substituted cycloalkyl; or
f) optionally substituted heterocyclyl; And
Each R &lt; ₂₅ &gt; is independently optionally substituted aryl; Optionally substituted arylalkyl, haloalkoxy, (haloalkoxy) alkyl, cycloalkyl, _{alkyl, -CH 2 CF 2 CF 3,} -CF 2 CF 3, or

/ RTI &gt; A compound of formula (XV), or a salt thereof, wherein:

Each R &lt; ₄ &gt; is independently aryl substituted with 0, 1, 2 or 3, independent R &lt; ₈ &gt;;
R ₅ is H, alkyl, phosphato, phosphito, alkoxy phosphato, or -C (O) alkyl optionally substituted with 1 or 2 amino;
Each R &lt; ₈ &gt; is independently optionally substituted alkyl, cyano, haloalkyl, alkoxy, halo, or haloalkoxy;
Each R &lt; ₃₆ &gt;

or

ego;
Each n is independently 1, 2, or 3;
Each p is independently 0, 1, 2, or 3;
Each R &lt; ₃₇ &gt; is independently halo, haloalkyl, or haloalkoxy;
Each R &lt; ₃₈ &gt; is independently:
a) 1, 2, or 3 independent OH, haloalkoxy, optionally substituted heterocyclo, optionally substituted heteroaryl,

,

,

,

,

,

,or

&Lt; / RTI &gt;
b) 0, 1, 2, or 3 independent OR ₁₇ or

&Lt; / RTI &gt;
c)

; or
d) optionally substituted heterocyclo;
Each R &lt; ₁₇ &gt; is independently H, optionally substituted alkyl, haloalkyl, or

ego;
Each R &lt; ₁₉ &gt; is independently H, optionally substituted alkyl, or haloalkyl;
Each R ₃₃ is independently H, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkylcarbonyl, or

/ RTI &gt; 4. The method according to any one of claims 1 to 3,
Wherein R &lt; ₅ &gt; is H. 4. The method according to any one of claims 1 to 3,
Wherein R &lt; ₅ &gt; is acyl substituted amino. 4. The method according to any one of claims 1 to 3,
Wherein R &lt; ₅ &gt; is phosphato. The method according to claim 1,
Wherein n is 1 and R &lt; ₃₅ &gt; is the 4-position of the phenyl ring in the formula XVI of claim 1. 3. The method of claim 2,
Wherein n is 1 and R &lt; ₃₀ &gt; is the 4-position of the phenyl ring in formula VII of claim 2. The method of claim 3,
Wherein R &lt; ₃₆ &gt; is at the 4-position of the phenyl ring in the formula XV of claim 3. The method according to claim 1,
Wherein said compound is one of the following:
(4- (2- (4 - ((6- (2- (2,4-difluorophenyl) -1,1-difluoro-2- ) Pyridin-3-yl) ethynyl) phenyl) -2-oxoethyl) benzonitrile (1) ;
Hydroxy-3- (lH-tetrazol-l-yl) propyl) pyridine-l- 3-yl) ethynyl) benzylamino) benzonitrile (2) ;
1- (5 - ((4 - ((2,2,2-tri &lt; / RTI &gt; Fluoroethylamino) methyl) phenyl) ethynyl) pyridin-2-yl) propan-2-ol (3) ;
Ethynyl) pyridin-2-yl) -2- (2,4-difluorophenyl) -1,1-difluoro- 3- (1H-tetrazol-1-yl) propan-2-ol (4) ;
1- (5 - ((4 - ((5- (trifluoromethyl) -1H-pyrazol- Thiophen-2-yl) methoxy) phenyl) ethynyl) pyridin-2-yl) propan-2-ol (5) ;
2- (2,4-difluorophenyl) -1,1-difluoro-1- (5 - ((4- ( 2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol (6) ;
Ethynyl) pyridin-2-yl) -2- (2,4-difluorophenyl) -1,1-difluoro- 3- (1H-tetrazol-1-yl) propan-2-ol (7) ;
2- (2,4-difluorophenyl) -1,1-difluoro-1- (5 - ((4- (4- fluorophenylamino) methyl) phenyl) ethynyl) pyridin- 3- (1H-tetrazol-1-yl) propan-2-ol (8) ;
2- (2,4-difluorophenyl) -1,1-difluoro-1- (5 - ((4- (4- (hydroxymethyl) benzyloxy) phenyl) ethynyl) pyridin- -3- (1H-tetrazol-1-yl) propan-2-ol (9) ;
1- (5 - ((4- (4 - ((2,2,2-trifluoroethoxy) phenyl) -1,1-difluoro- 2-trifluoroethoxy) methyl) benzyloxy) phenyl) ethynyl) pyridin-2-yl) propan-2-ol (10) ;
2- (2,4-difluorophenyl) -1- (5 - ((4- (4- (dimethylamino) methyl) benzyloxy) phenyl) ethynyl) pyridin- Difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (11) ;
Hydroxy-3- (1H-tetrazol-1-yl) -1H-pyrazole-3- Propyl) pyridin-3-yl) ethynyl) phenoxy) methyl) benzyl) acetamide (12) ;
Ethynyl) pyridin-2-yl) -2- (2,4-difluoro-phenyl) ) -1,1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (13) ;
1- (5 - ((4- (4 - ((2,2,2-trifluoroethoxy) phenyl) -1,1-difluoro- 2-trifluoroethylamino) methyl) benzyloxy) phenyl) ethynyl) pyridin-2-yl) propan-2-ol (14) ;
Ethynyl) pyridin-2 (2-hydroxyphenyl) -1,1-difluoro-1- (5- Yl) -3- (1H-tetrazol-1-yl) propan-2-ol (15) ;
2- (4 - ((4 - ((6- (2- (2,4-difluorophenyl) -1,1-difluoro-2- Propyl) pyridin-3-yl) ethynyl) phenoxy) methyl) phenoxy) acetic acid (16) ;
(4- (2- (4 - ((6- (2- (2,4-difluorophenyl) -1,1-difluoro-2- ) Pyridin-3-yl) ethynyl) phenyl) -2-oxoethyl) -2-fluorobenzonitrile (17) ;
Ethynyl) pyridin-2-yl) -2- (2,4-difluorophenyl) -1,1 (dimethylamino) - difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (18) ;
2- (4-chloro-3-fluorophenyl) -1- (4 - ((6- (2- (2,4-difluorophenyl) -1,1- difluoro-2- Yl) propyl) pyridin-3-yl) ethynyl) phenyl) ethanone (19) ;
2- (4 - ((4 - ((6- (2- (2,4-difluorophenyl) -1,1-difluoro-2- Propyl) pyridin-3-yl) ethynyl) phenoxy) methyl) benzylamino) acetic acid (20) ;
2- (2,4-difluorophenyl) -1- (5 - ((4- (4 - ((ethylamino) methyl) benzyloxy) phenyl) ethynyl) pyridin- Difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (21) ;
(5 - ((4- (4 - ((methylamino) methyl) benzyloxy) phenyl) ethynyl) pyridin- 2- Yl) -3- (1H-tetrazol-1-yl) propan-2-ol (22) ;
1- (5 - ((4- (4- (pyrrolidin-1-ylmethyl) benzyloxy) phenyl) ethynyl) pyridine -2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol (23) ;
Synthesis of 2- (2,4-difluorophenyl) -1,1-difluoro-1- (5 - ((4- (4- ((oxazol- 2- ylamino) methyl) benzyloxy) phenyl) ethynyl ) Pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol (24) ;
2- (2,4-difluorophenyl) -1,1-difluoro-1- (5- (4- (4- (1-hydroxyethyl) benzyloxy) phenyl) ethynyl) Yl) -3- (1H-tetrazol-1-yl) propan-2-ol (25) ;
1- (5 - ((4- (4- (2,2,2-trifluoro-phenyl) -1,1-difluoro-3- -Trifluoro-1-hydroxyethyl) benzyloxy) phenyl) ethynyl) pyridin-2-yl) propan-2-ol (26) ;
Yl) methoxy) phenyl) ethynyl) pyridin-2 (2S) -2 - [(4- -Yl) -1,1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (27) ;
Hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridine-1-carboxylic acid 3-yl) ethynyl) phenyl) -2- (4 - ((dimethylamino) methyl) phenyl) ethanone (28) ;
2-yl) -2- (2,4-difluoroethoxy) methyl) benzyloxy) phenyl) ethynyl) pyridin- ) -1,1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (29) ;
2- (4 - ((4 - ((6- (2- (2,4-difluorophenyl) -1,1-difluoro-2- Propyl) pyridin-3-yl) ethynyl) phenoxy) methyl) benzyloxy) acetonitrile (30) ;
Methyl) phenyl) ethynyl) pyridin-2-yl) -1- (5 - ((4 - ((dimethylamino) , 1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (31) ;
2- (4 - ((4 - ((6- (2- (2,4-difluorophenyl) -1,1-difluoro-2- Propyl) pyridin-3-yl) ethynyl) phenoxy) methyl) benzylamino) acetonitrile (32) ;
Hydroxy-3- (1H-tetrazol-1-yl) -1H-pyrazole-3- Propyl) pyridin-3-yl) ethynyl) phenoxy) methyl) benzyl) -1H-pyrazole-4-carbonitrile (33) ;
Ethynyl) pyridin-2-yl) -2- (2, 4-dihydroxyphenyl) - difluorophenyl) -1,1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (34) ;
Ethynyl) pyridin-2-yl) -2- (2, 4-dihydroxyphenyl) (Difluorophenyl) -1,1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (35) ;
Fluoro-1H-pyrazol-1-yl) methyl) benzyloxy) -1- (5 - ((4- (4- ) Phenyl) ethynyl) pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol (36) ;
1- (5 - ((4- (4 - ((4- (2-methoxyethyl) -1 H-pyrazole-1- Yl) methyl) benzyloxy) phenyl) ethynyl) pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol (37) ;
N - ((1- (4 - ((4- (6- (2- (2,4-difluorophenyl) -1,1- difluoro-2- Yl) propyl) pyridin-3-yl) ethynyl) phenoxy) methyl) benzyl) -1H-pyrazol-3-yl) methyl) acetamide (38) ;
1 -difluoro-1- (5 - ((4- (4 - ((4- (2-hydroxypropan- Yl) methyl) benzyloxy) phenyl) ethynyl) pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol (39) ;
1- (5 - ((4- (4 - ((4- (1 -hydroxyethyl) -1H-pyrazole-1- Yl) methyl) benzyloxy) phenyl) ethynyl) pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol (40) ;
Hydroxy-3- (1H-tetrazol-1-yl) -1H-pyrazole-3- Propyl) pyridin-3-yl) ethynyl) phenoxy) methyl) benzyl) -1H-pyrazole-4-carboxylic acid (41) ;
Methyl) benzyloxy) phenyl) -1,1-difluoro-1- (5 - ((4- (4- ( ) Ethynyl) pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol (42) ;
2 - ((4 - ((4 - ((6- (2- (2,4-difluorophenyl) -1,1-difluoro-2- ) Propyl) pyridin-3-yl) ethynyl) phenoxy) methyl) benzyl) (methyl) amino) acetonitrile (43) ;
Trifluoroethyl) amino] methyl} benzyl (2-methyl-2-oxoethyl) Oxy) phenyl) ethynyl) pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol (44) ;
Phenyl) ethynyl) pyridin-2-yl) -2- (4-fluorophenyl) (2,4-difluorophenyl) -1,1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (45) ;
Methyl) amino) methyl &lt; RTI ID = 0.0 &gt; (2, &lt; / RTI &gt; ) Benzyloxy) phenyl) ethynyl) pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol (46) ;
(5 - ((4- (4 - ((2-hydroxypropyl) (methyl) amino) methyl) benzyloxy) -1,1-difluoro- Phenyl) ethynyl) pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol (47) ;
2 - ((4 - ((4 - ((6- (2- (2,4-difluorophenyl) -1,1-difluoro-2- ) Propyl) pyridin-3-yl) ethynyl) phenoxy) methyl) benzylamino) methyl) -1H-imidazole-1-carbaldehyde (48) ;
2 - (((4 - ((4 - ((6- (2- (2,4-difluorophenyl) -1,1-difluoro-2- Yl) propyl) pyridin-3-yl) ethynyl) phenoxy) methyl) benzyl) (methyl) amino) methyl) -1H-imidazole-1-carbaldehyde (49) ;
Hydroxy-3- (1H-tetrazol-1-yl) -1H-pyrazole-3- Propyl) pyridin-3-yl) ethynyl) phenoxy) methyl) benzyl) -1H-imidazole-4-carbonitrile (50) ;
Hydroxy-3- (1H-tetrazol-1-yl) -1H-pyrazole-3- Propyl) pyridin-3-yl) ethynyl) phenoxy) methyl) benzyl) -N-methyl-1H-imidazole-2-carboxamide 51 ;
Phenyl) -1,1-difluoro-1- (5 - ((4- (4-methylpiperazin-1-yl) methyl) benzyloxy) phenyl) Ethynyl) pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol (52) ;
Hydroxy-3- (1H-tetrazol-1-yl) -1H-pyrazole-3- Propyl) pyridin-3-yl) ethynyl) phenoxy) methyl) benzyl) piperazine-1-carbaldehyde (53) ;
Ethynyl) pyridin-2-yl (4-fluorophenyl) -1,1-difluoro-1- ) -3- (1H-tetrazol-1-yl) propan-2-ol (54) ;
Hydroxy-3- (1H-tetrazol-1-yl) -1H-pyrazole-3- Propyl) pyridin-3-yl) ethynyl) phenoxy) methyl) benzyl) imidazolidin-2-one (55) ;
Hydroxy-3- (1H-tetrazol-1-yl) -1H-pyrazole-3- Propyl) pyridin-3-yl) ethynyl) phenoxy) methyl) benzyl) imidazolidin-2,4-dione (56) ;
Ethynyl) pyridin-2-yl) -2- (2,4-di (tert-butyldimethylsilyloxy) Fluorophenyl) -1,1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (57) ;
(4- (2- (4 - ((6- (2- (2,4-difluorophenyl) -1,1-difluoro-2- ) Pyridin-3-yl) ethynyl) phenyl) -2-hydroxyethyl) benzonitrile (58) ;
Hydroxy-3- (1H-tetrazol-1-yl) -1H-pyrazole-3- (4H) -2-methylpentan-3-yl) -1H-1,2,4-triazole-5 (4H) ) -One (59) ;
(2-hydroxy-1- (1H-pyrazol-1-yl) ethyl) -1,1-difluoro-1- (5- ) Benzyloxy) phenyl) ethynyl) pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol (60) ;
2- (2,4-difluorophenyl) -1- (5 - ((4- (4- (1- (dimethylamino) -2-hydroxyethyl) phenyl) ethynyl) pyridin- Yl) -1,1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (61) ;
Ethynyl) pyridin-2-yl) -1- (5 - ((4- (3- (hydroxymethyl) benzyloxy) phenyl) -3- (1H-tetrazol-1-yl) propan-2-ol (62) ;
2- (2,4-difluorophenyl) -1- (5 - ((4- (3 - ((dimethylamino) methyl) benzyloxy) phenyl) ethynyl) pyridin- Difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (63) ;
Ethynyl) pyridin-2-yl) -2- (2,4-difluoro-phenyl) ) -1,1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (64) ;
2- (2,4-difluorophenyl) -1- (5 - ((4- (3- (1- (dimethylamino) -2-hydroxyethyl) phenyl) ethynyl) Yl) -1,1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (65) ;
(2-hydroxy-1- (1H-pyrazol-1-yl) ethyl) -1,1-difluoro-1- (5- ) Benzyloxy) phenyl) ethynyl) pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol (66) ;
Phenyl) ethynyl) pyridin-2-yl) - (3-chloro-lH- 2- (2,4-difluorophenyl) -1,1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (67) ;
2- (2,4-difluorophenyl) -1- (5 - ((4- ((5 - ((dimethylamino) methyl) thiophen-2- yl) methoxy) phenyl) ethynyl) Yl) -1,1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (68) ;
Yl) methoxy) phenyl) ethynyl) pyridin-2-yl) -2- (4-fluorophenyl) (2,4-difluorophenyl) -1,1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (69) ;
Ethynyl) pyridin-2-yl) -2- (2, 4-difluorophenyl) ethoxy] ) -1,1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (73) ;
Ethynyl) pyridin-2-yl) -2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (74) ;
2- (2,4-difluorophenyl) -1,1-difluoro-1- (5 - ((4- (4-chlorophenyl) Yl) -3- (1H-tetrazol-1-yl) propan-2-ol (79) ;
1- (5 - ((4- (2- (4-chlorophenyl) -1-hydroxyethyl) phenyl) ethynyl) pyridine Yl) -3- (1H-tetrazol-1-yl) propan-2-ol (80) ;
(5 - ((4- (1-hydroxy-2- (2,2,2-trifluoroethoxy) ethyl) -1,1- Phenyl) ethynyl) pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol 81 ;
Hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridine-1-carboxylic acid 3-yl) ethynyl) phenyl) -3,3,4,4,4-pentafluorobutan-1-ol (82) ;
Ethynyl) pyridin-2-yl) -2- (2, 4-difluorophenyl) ) -1,1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (83) ;
(1 - (4 - ((6- (2- (2,4-difluorophenyl) -1,1-difluoro-2- ) Pyridin-3-yl) ethynyl) phenyl) propyl) -1,1,1-trifluoromethanesulfonamide (84) ;
Hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridine-1-carboxylic acid 3-yl) ethynyl) phenyl) -3- (dimethylamino) -2,2-difluoropropan-1-ol (85) ;
2-yl) -2- (2,4-difluorophenyl) -1,1-difluoro-3 (trifluoromethyl) - (1H-tetrazol-1-yl) propan-2-ol (86) . 3. The method of claim 2,
Wherein said compound is one of the following:
Methyl-1,1-difluoro-2-hydroxy-3-methylbutyl) pyridin-3-yl) Ethynyl) phenoxy) methyl) benzonitrile (70);
Methyl-1,1-difluoro-2-hydroxy-3,3-dimethylbutyl) pyridine-3- Yl) ethynyl) phenoxy) methyl) benzonitrile (71);
4 - ((4 - ((6- (2-cyclopropyl-1,1-difluoro-2-hydroxy- ) Phenoxy) methyl) benzonitrile (72). The method of claim 3,
Wherein said compound is one of the following:
2- (2,4-difluorophenyl) -1- (5 - ((4- (4 - ((dimethylamino) methyl) -3-fluorobenzyloxy) phenyl) ethynyl) pyridin- 1,1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (75) ;
Ethynyl) pyridin-2-yl) -2- (2,4-difluorophenyl) -1- (5 - ((4- (4- fluorophenyl) , 1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (76) ;
Ethynyl) pyridin-2-yl) -2- (2, 4-dihydro- - difluorophenyl) -1,1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (77) ;
Ethynyl) pyridin-2-yl) -2- (4-fluoro-4- (4- (4- (2,4-difluorophenyl) -1,1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (78). 13. The method according to any one of claims 1 to 12,
The compound may be a compound having affinity for a metal enzyme by one or more of chemical interactions or formation of a bond with a metal, such as: sigma bond, covalent bond, coordination bond, ionic bond, pi bond, delta bond, Backbonding interaction. 13. The method according to any one of claims 1 to 12,
Wherein said compound is bonded to a metal. 13. The method according to any one of claims 1 to 12,
Wherein the compound is bonded to iron, zinc, heme iron, manganese, magnesium, iron sulfide clusters, nickel, molybdenum, or copper. 13. The method according to any one of claims 1 to 12,
The compound inhibits one enzyme group selected from the group of cytochrome P450, histone deacetylase, substrate metalloproteinase, phosphodiesterase, cyclooxygenase, carbonic anhydrase, and nitric oxide synthase . 13. The method according to any one of claims 1 to 12,
The compound is preferably selected from the group consisting of 4-hydroxyphenylpyruvate deoxygenase, 5-lipoxygenase, adenosine deaminase, alcohol dehydrogenase, aminopeptidase N, angiotensin converting enzyme, aromatase (CYP19) Carbamoyl phosphate synthase, carbanic anhydraze, catecholomethyltransferase, cyclooxygenase, dihydropyrimidine dihydrogenase-1, DNA polymerase, parnecyldiphosphate synthase, HIV-1 reverse transcriptase, isoleucine tRNA ligase, GABA aminotransferase, HIF-prolyl hydroxylase, histone deacetylase, HIV integrase, HIV-1 reverse transcriptase, , Lanosterol dimethylazate (CYP51), substrate metalloprotease family, methionine aminopeptidase, neutral endopeptidase, nitric oxide synthase , Phosphodiesterase III, phosphodiesterase IV, phosphodiesterase V, pyruvate ferredoxin oxydoridase, kidney peptidase, ribonucleoside diphosphate reductase, thromboxane synthase (CYP5a), thyroid Wherein the enzyme inhibits one enzyme selected from peroxidase, tyrosinase, urease, or xanthine oxidase. 13. The method according to any one of claims 1 to 12,
The compounds are selected from the group consisting of 1-deoxy-d-xylulose-5-phosphate reductoisomerase (DXR), 17- alphahydroxylase / 17,20- lyase (CYP17), aldosterone synthase (CYP11B2), aminopeptidase P, anthracnose lethal factor, arginase, beta-lactamase, cytochrome P450 2A6, d-alan-d-alligase, dopamine- beta -hydroxylase, endothelin- 1, glutamate carboxypeptidase II, glutaminyl cyclase, glyoxalase, hemoxigenase, HPV / HSV E1 helicase, indoleamine 2,3-deoxygenase, leukotriene A4 hydrolase, methionine amino (CYP26), TNF-alpha converting enzyme (TACE), UDP- (3-O- (R-3-hydroxypyridyloxyphenyl) phosphite, peptidase 2, peptide dexamylase, phosphodiesterase VII, relexase, retinoic acid hydroxylase Myristoyl) - N-acetylglucosamine deacetylase (LpxC), vascular adhesion protein-1 (VAP-1), and Lt; / RTI &gt; inhibits an enzyme selected from vitamin D hydroxylase (CYP24). 13. The method according to any one of claims 1 to 12,
Wherein said compound is identified by binding to a metal. 13. The method according to any one of claims 1 to 12,
Wherein the compound is identified by binding to iron, zinc, heme iron, manganese, magnesium, iron sulphide clusters, nickel, molybdenum, or copper. 13. The method according to any one of claims 1 to 12,
The compound inhibits one enzyme group selected from the group of cytochrome P450, histone deacetylase, substrate metalloproteinase, phosphodiesterase, cyclooxygenase, carbonic anhydrase, and nitric oxide synthase &Lt; / RTI &gt; 13. The method according to any one of claims 1 to 12,
The compound is preferably selected from the group consisting of 4-hydroxyphenylpyruvate deoxygenase, 5-lipoxygenase, adenosine deaminase, alcohol dehydrogenase, aminopeptidase N, angiotensin converting enzyme, aromatase (CYP19) Carbamoyl phosphate synthase, carbanic anhydraze, catecholomethyltransferase, cyclooxygenase, dihydropyrimidine dihydrogenase-1, DNA polymerase, parnecyldiphosphate synthase, HIV-1 reverse transcriptase, isoleucine tRNA ligase, GABA aminotransferase, HIF-prolyl hydroxylase, histone deacetylase, HIV integrase, HIV-1 reverse transcriptase, , Lanosterol dimethylazate (CYP51), substrate metalloprotease family, methionine aminopeptidase, neutral endopeptidase, nitric oxide synthase , Phosphodiesterase III, phosphodiesterase IV, phosphodiesterase V, pyruvate ferredoxin oxydoridase, kidney peptidase, ribonucleoside diphosphate reductase, thromboxane synthase (CYP5a), thyroid Wherein the compound is identified by inhibiting one enzyme selected from peroxidase, tyrosinase, urease, or xanthine oxidase. 13. The method according to any one of claims 1 to 12,
Wherein said compound is identified by inhibiting (or inhibiting) lanosterol demethyl neuase (CYP51). 13. The method according to any one of claims 1 to 12,
The compound is a C. albicans 0.0 &gt; mg / mL &lt; / RTI &gt; and A. fumigatus MIC &amp;le; 64 mu g / mL. 13. A method for inhibiting metal enzyme activity comprising contacting a compound according to any one of claims 1 to 12 with a metal enzyme. 26. The method of claim 25,
Wherein said contacting occurs in vivo. 26. The method of claim 25,
Wherein said contacting occurs in vitro. 26. The method of claim 25,
Wherein the metal enzyme comprises a metal atom that is iron, zinc, heme iron, manganese, magnesium, iron sulphide clusters, nickel, molybdenum, or copper. 26. The method of claim 25,
Wherein said metal enzyme is selected from the group consisting of a group of enzymes selected from the group consisting of cytochrome P450 family, histone deacetylase, substrate metalloproteinase, phosphodiesterase, cyclooxygenase, carbonic anhydrase, and nitric oxide synthase How to be a member. 26. The method of claim 25,
Wherein said metal enzyme is lanosterol demethylase (CYP51). 26. The method of claim 25,
The metal enzyme may be selected from the group consisting of 4-hydroxyphenylpyruvate dioxygenase, 5-lipoxygenase, adenosine deaminase, alcohol dehydrogenase, aminopeptidase N, angiotensin converting enzyme, aromatase (CYP19) , Carbamoyl phosphate synthase, carnonic anhydrazae, catechol-omethyltransferase, cyclooxygenase, dihydropyrimidine dihydrogenase-1, DNA polymerase, parnaceyl diphosphate HIF-prolyl hydroxyase, histone deacetylase, HIV integrase, HIV-1 reverse transcriptase, isoleucine, isoleucine, isoleucine, tRNA ligase, lanosterol dimethylazae (CYP51), substrate metalloprotease family, methionine aminopeptidase, neutral endopeptidase, nitric oxide synthase Phosphodiesterase III, phosphodiesterase IV, phosphodiesterase V, pyruvate ferredoxin oxydoryldactase, renal peptidase, ribonucleoside diphosphate reductase, thromboxane synthase (CYP5a), tyrosine kinase Lyxedoxidase, tyrosinase, urease, or xanthine oxidase. 26. The method of claim 25,
The metal enzyme may be selected from the group consisting of 1-deoxy-d-xylulose-5-phosphate reductoisomerase (DXR), 17-alphahydroxylase / 17,20- lyase (CYP17), aldosterone synthase Beta] -hydroxylase, endothelin-converting enzyme (CYP11B2), aminopeptidase P, anthracnose lethal factor, arginase, beta-lactamase, cytochrome P450 2A6, d- -1, glutamate carboxypeptidase II, glutaminyl cyclase, glyoxalase, hemoxigenase, HPV / HSV E1 helicase, indoleamine 2,3-dioxygenase, leukotriene A4 hydrolase, methionine (3-O- (R-3-hydroxycyclohexylmethyl) -transferase (TACE), aminopeptidase 2, peptide dexamylase, phosphodiesterase VII, relexase, retinoic acid hydroxylase (LpxC), vascular adhesion protein-1 (VAP-1), &lt; RTI ID = Or vitamin D hydroxylase (CYP24). 26. The method of claim 25,
&Lt; / RTI &gt; further comprising administering the compound to a subject. 26. The method of claim 25,
Wherein the compound of formula (I) is a compound identified by having an activity range of C. albicans MIC < 1.0 μg / mL and A. fumigatus MIC ≤ 64 μg / mL. The method comprising contacting a subject with a compound according to any one of claims 1 to 24 in an amount sufficient to modulate a metal enzyme activity under conditions sufficient to modulate a metal enzyme activity, Way. 24. A method of treating a subject having or susceptible to a metal enzyme-related disorder or disease, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 24. Comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 24 for the treatment of a metal enzyme-related disorder or disease, Wherein said subject is identified as requiring treatment of a metal enzyme-related disorder or disease. Comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 24 for the purpose of modulating (e.g., down-regulating, inhibiting) Wherein the subject is identified as requiring treatment of a metal enzyme-related disorder or disease. 39. The method of claim 38,
The disease or disorder is selected from the group consisting of 4-hydroxyphenylpyruvate deoxygenase, 5-lipoxygenase, adenosine deaminase, alcohol dehydrogenase, aminopeptidase N, angiotensin converting enzyme, aromatase (CYP19) Neurin, carbamoyl phosphate synthase, carbonic anhydrase, catechol-methyltransferase, cyclooxygenase, dihydropyrimidine dihydrogenase-1, DNA polymerase, parnecyldiphosphate HIF-prolyl hydroxyase, histone deacetylase, HIV integrase, HIV-1 reverse transcriptase, isoleucine, isoleucine, isoleucine, tRNA ligase, lanosterol dimethylazate (CYP51), substrate metalloprotease family, methionine aminopeptidase, neutral endopeptidase, nitric oxide Phosphodiesterase III, phosphodiesterase IV, phosphodiesterase V, pyruvate ferredoxin oxidoreductase, renal peptidase, ribonucleoside diphosphate reductase, thromboxane synthase (CYP5a), Thyroid peroxidase, tyrosinase, urease, or xanthine oxidase. 39. The method of claim 38,
Wherein said disease or disorder is selected from the group consisting of 1-deoxy-d-xylulose-5-phosphate reductoisomerase (DXR), 17-alphahydroxylase / 17,20-lyase (CYP17) (CYP11B2), aminopeptidase P, anthracnose lethal factor, arginase, beta-lactamase, cytochrome P450 2A6, d-alan-d-allergicase, dopamine-beta-hydroxyalase, endothelin conversion Enzyme-1, glutamate carboxypeptidase II, glutaminyl cyclase, glyoxalase, hemoxigenase, HPV / HSV E1 helicase, indoleamine 2,3-deoxygenase, leukotriene A4 hydrolase, (CYP26), TNF-alpha converting enzyme (TACE), UDP- (3-O- (R-3- N-acetylglucosamine deacetylase (LpxC), vascular adhesion protein-1 VAP-1), or vitamin D hydroxylase (CYP24). 39. The method of claim 38,
Wherein the disease or disorder is cancer, a cardiovascular disease, an endocrine system disease, an inflammatory disease, an infectious disease, a gynecological disease, a metabolic disease, an ophthalmic disease, a central nervous system (CNS) disease, a urological disease or gastrointestinal disease. 39. The method of claim 38,
Wherein the disease or disorder is systemic mycosis, or parasitic fungus. 24. A composition comprising a compound according to any one of claims 1 to 24 and an agriculturally acceptable carrier. A method for treating or preventing a metal enzyme-related disease or disorder on a plant or plant, comprising contacting the plant or seed with a compound according to any one of claims 1 to 24. 24. A method for inhibiting metalloenzyme activity in a plant microorganism comprising contacting a plant or seed with a compound according to any one of claims 1 to 24. 24. A method for treating or preventing a fungal disease or disorder in or on a plant, comprising contacting the plant or seed with a compound according to any one of claims 1 to 24. 24. A method for treating or preventing fungal growth in or on a plant comprising contacting a plant or seed with a compound according to any one of claims 1 to 24. 24. A method for inhibiting microorganisms in plants or plants, comprising contacting a plant or seed with a compound according to any one of claims 1 to 24. 44. The method of claim 43,
But are not limited to, epoxiconazole, tebuconazole, fluquinconazole, flutriafol, metconazole, myclobutanil, cycproconazole, ), Prothioconazole, and propiconazole. &Lt; Desc / Clms Page number 11 &gt; 44. The method of claim 43,
Further include strobilurin fungicide in the group of trifloxystrobin, pyraclostrobin, orysastrobin, fluoxastrobin, and azoxystrobin group. / RTI &gt; 24. A composition comprising a compound according to any one of claims 1 to 24 and a pharmaceutically acceptable carrier. 52. The method of claim 51,
A composition comprising an additional therapeutic agent. 52. The method of claim 51,
The anti-inflammatory agent may be an anti-cancer agent, an antifungal agent, a cardiovascular agent, an anti-inflammatory agent, a chemotherapeutic agent, an anti-angiogenesis agent, (CNS) disease agent, a cytotoxic agent, an anti-proliferation agent, a metabolic disease agent, an ophthalmologic disease agent, A therapeutic agent, a urologic disease agent, or a gastrointestinal disease agent. 24. A method for treating a subject suffering from or susceptible to a disorder or disease, comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 24, &Lt; / RTI &gt; 55. The method of claim 54,
Wherein said disorder or disease is associated with one or more of the following pathogenic fungi:
Aptodiakorimbi Ferra, Azelam Isis Dermatidis, Arturo Aleman Benhamiae, Arturo Admiral Fumboom, Arturo Admiral Gibsium, Arturo de Mallin Kurbatum, Arturo de Mazota, Arturo Aspergillus Fumigates, Aspergillus Niger, Blastomycetes Dermatitidis, Candida albicans, Candida glabrata, Candida giardi Mondi, Candida Candida albicans, Candida albicans, Candida albicans, Candida albicans, Candida albicans, Candida albicans, Candida albicans, Candida albicans, Candida albicans, Candida albicans, Candida albicans, Candida albicans, Candida albicans, Candida albicans, Candida albicans, Candida albicans, Candida parapthoxalis, Candida tropicallis, Candida pelliculosa, Blessed be the name of the Lord of the Rings of the earth, and of the flesh of the flesh, To Plasma Capsule Reutomu, Horthe Warwick, Ischsche Kia Orientalis, Madulele Grisis, Malasejia Furfur, Malasejia Globosa, Malasejia of Fusa, Malasejia Parkie the Matisse, Malasejia , Mucroseum Cocaine, Mycrosporum Fulombaum, Mycrosporum Gibsemum, Mucorcissineloid, Nectria Hematocococcus, Pesylomai Mecrosis, Roussopoulos, Roussopoulos, Roussillon, Roussillon, Roussillon, Roussillon, Roussillon, Roussillon, Roussillon, Laura Bra, Sedrosporium Apios Fungum, Sijo Philium Cocoon, Sporotric Senki, Tricophyton Mentagrophytes, Tricophyton Lubrum, Trico Piton Vulcus, Tricophyton Viola , Tree courses Asahi isophorone, isophorone Tree courses Kuta Neum, tree inkin course isophorone, isophorone deuseu mukoyi Tree courses. 55. The method of claim 54,
Wherein said disorder or disease is selected from the group consisting of aspergillosis, fluticasone, candidiasis, pigment fungi, coccidioidomycosis, cryptococcosis, dermatophytosis, histoplasmosis, corneal mycosis, , Hair folliculitis, paracoxidioid infections, Penicillium marneffey infections, pero hypomacosis infections, neomycostasis pneumonias, or linosporidiosis. 55. The method of claim 54,
The disorder or disease is selected from the group consisting of Chagas disease (T. typhimurium), T. typhimurium, T. rehmanniae, M. tuberculosis (Mycobacterium), Hansen's disease (Mycobacterium), Malaria ), Or tinea (tinea tinea, body tinea, athlete's foot, tonnage, wind). 55. The method of claim 54,
Wherein said subject is an animal other than a human.